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Posts Tagged ‘monoclonal antibody’


Chemotherapy in AML

Curator: Larry H. Bernstein, MD, FCAP

 

 

Sorafenib Showed Efficacy as Chemotherapy Add-On in AML
Results from the phase II SORAML trial indicated that adding sorafenib to standard chemotherapy for younger patients with acute myeloid leukemia was effective, but also resulted in increased toxicity

Reduced-Intensity HSCT Extends Remission in Older AML Patients
The use of reduced-intensity conditioning HSCT as a method to maintain remission was effective in a select group of older patients with acute myeloid leukemia

 

Sorafenib Showed Efficacy as Chemotherapy Add-On in AML

– See more at: http://www.cancernetwork.com/leukemia-lymphoma/sorafenib-showed-efficacy-chemotherapy-add-aml

 

Results from the phase II SORAML trial indicated that adding sorafenib to standard chemotherapy for younger patients with acute myeloid leukemia (AML) was effective, but also resulted in increased toxicity.

 

The drug increased event-free survival and reduced need for salvage therapy and allogeneic stem cell transplantation, but also produced worse grade 3 or higher fever, diarrhea, bleeding, cardiac events, and rash compared with placebo.

“After a decade of assessing the potential of kinase inhibitors in acute myeloid leukemia, their use in combination with standard treatment is becoming an important option for newly diagnosed younger patients,” wrote Christoph Röllig, MD, of Medizinische Klinik und Poliklinik I, Universitätsklinikum der Technischen Universität in Dresden, Germany, and colleagues in Lancet Oncology.

Patients age 18 to 60 years were enrolled in the phase II study between 2009 and 2011. All patients had to have newly diagnosed, treatment-naive AML and a performance status of 0–2. Patients were randomly assigned to 2 cycles of induction daunorubicin plus cytarabine followed by 3 cycles of high-dose cytarabine consolidation therapy plus either sorafenib 400 mg twice daily (n = 134) or placebo (n = 133).

With a median follow-up of 3 years, the researchers found that adding sorafenib to standard chemotherapy significantly improved event-free survival, from a median of 9 months with placebo to a median of 21 months with sorafenib. Patients assigned sorafenib had a 3-year event-free survival rate of 40% compared with 22% for patients assigned placebo (P = .013).

“The improvement in event-free survival and relapse-free survival is significant and clinically relevant since salvage treatment with or without allogeneic stem cell transplantation could be prevented or substantially delayed by sorafenib treatment,” the researchers wrote.

At 3 years, 63% of patients assigned sorafenib and 56% of patients assigned placebo were still alive, and the median overall survival was not reached in either group. Patients assigned sorafenib had fewer relapses after complete remission compared with placebo (54 vs 34) and, therefore, fewer allogeneic stem cell transplantations were required among patients assigned sorafenib (31 vs 18).

Finally, withdrawal from the trial due to adverse events was more common among patients assigned sorafenib (24% vs 12%).

In an editorial published with the study, Naval Daver, MD, and Marina Konopleva, MD, PhD, of the University of Texas MD Anderson Cancer Center in Houston, pointed out that these results contrast findings by Serve et al who found that “the addition of sorafenib to standard chemotherapy in patients older than 60 years with acute myeloid leukemia resulted in increased toxicity and early mortality,” without improved antileukemic efficacy compared with placebo, suggesting that older patients were unable to tolerate the toxicities associated with the addition of sorafenib to standard chemotherapy.

Daver and Konopleva agreed with Röllig and colleagues, writing that the lack of improvement in overall survival despite an improvement in event-free survival requires “further investigation to develop future strategies that will improve overall survival.”

 

Sorafenib and novel multikinase inhibitors in AML

Naval Daver, Marina Konopleva

The Lancet Oncology 2015.          DOI: http://dx.doi.org/10.1016/S1470-2045(15)00454-4

Induction chemotherapy can produce complete remission in most (50–70%) patients with acute myeloid leukaemia.1 However, between 50% and 80% of patients relapse, and only 20–30% achieve long-term disease-free survival.

 

Reduced-Intensity HSCT Extends Remission in Older AML Patients

– See more at: http://www.cancernetwork.com/leukemia-lymphoma/reduced-intensity-hsct-extends-remission-older-aml-patients

 

The use of reduced-intensity conditioning hematopoietic stem cell transplantation (HSCT) as a method to maintain remission was effective in a select group of older patients with acute myeloid leukemia (AML), resulting in a nonrelapse mortality (NRM) similar to that seen in younger patients, according to the results of the phase II Cancer and Leukemia Group B 100103/Blood and Marrow Transplant Clinical Trial Network 0502 trial. 

 

“Of critical importance, for the first time (to the best of our knowledge), favorable results in transplantation of older patients have been obtained in a multicenter cooperative group setting, which makes the results more likely to be generalizable,” wrote Steven M. Devine, MD, of the Ohio State University in Columbus, Ohio, and colleagues in the Journal of Clinical Oncology.

According to the study, although patients aged older than 60 have complete remission rates of 50% to 60%, many will ultimately relapse. HSCT is associated with lower rates of relapse compared with chemotherapy in younger patients, but has been considered too toxic for older patients.

This study looked at the use of reduced-intensity conditioning HSCT in an older patient population aged 60 to 74 years. It included 114 patients with AML who were in first complete remission. The median age of patients was 65 years. A little more than half of the patients received transplants from unrelated donors and were given rabbit antithymocyte globulin (ATG) for graft-versus-host disease (GVHD) prophylaxis.

At follow-up, 71 patients had died. The median follow-up of the 43 surviving patients was 1,602 days. At 2 years, the rate of disease-free survival (DFS) was 42% and overall survival (OS) was 48%. Among patients who had unrelated donors, the 2-year DFS was 40% and the OS was 50%.

“The 2-year DFS and OS rates in this group compare favorably to those in studies of conventional chemotherapy–based approaches to remission consolidation in which DFS and OS rates beyond 2 years are typically below 20%,” the researchers wrote.

The NRM at 2 years was 15% and was not different among those patients with related vs unrelated donors. Forty-four percent of patients relapsed at 2 years.

“The 44% relapse rate at 2 years was high, although relapse rates approaching 80% to 90% have been observed in older patients after conventional chemotherapy, suggesting a potential graft-versus-leukemia effect,” the researchers wrote. “Interpretation of our trial results is limited somewhat by lack of consistent knowledge of the mutational status of the patients at diagnosis or of disease burden at complete remission by minimal residual disease assessment.”

There was a cumulative incidence of grades 2 to 4 GVHD of 9.6% and of grade 3 to 4 GVHD of 2.6% at 100 days. The incidence of GVHD did not vary by donor type. Chronic GVHD occurred in 28% of patients.

Devine and colleagues noted that these rates were lower than they anticipated.

“The incorporation of rabbit ATG into the conditioning regimen for all patients, including recipients with matched sibling donors, may have contributed to the relatively low rates of GVHD and NRM, as has been observed in previous studies,” they wrote.

 

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Diabetic Retinopathy

Larry H. Bernstein, MD, FCAP, Curator

LPBI

 

Lucentis effective for proliferative diabetic retinopathy

NIH-funded clinical trial marks first major advance in therapy in 40 years.

http://www.nih.gov/news-events/news-releases/lucentis-effective-proliferative-diabetic-retinopathy

Illustration of ruptured blood vessels

http://www.nih.gov/sites/default/files/styles/featured_media_breakpoint-large-extra/public/news-events/news-releases/2015/20151116-eye-blood-vessels.jpg

Abnormal blood vessels bleeding into the center of the eye due to proliferative diabetic retinopathy.

https://youtu.be/jPoCIa0_1po

A clinical trial funded by the National Institutes of Health has found that the drug ranibizumab (Lucentis) is highly effective in treating proliferative diabetic retinopathy. The trial, conducted by the Diabetic Retinopathy Clinical Research Network (DRCR.net) compared Lucentis with a type of laser therapy called panretinal or scatter photocoagulation, which has remained the gold standard for proliferative diabetic retinopathy since the mid-1970s. The findings demonstrate the first major therapy advance in nearly 40 years.

“These latest results from the DRCR Network provide crucial evidence for a safe and effective alternative to laser therapy against proliferative diabetic retinopathy,” said Paul A. Sieving, M.D., Ph.D., director of NIH’s National Eye Institute (NEI), which funded the trial.  The results were published online today in the Journal of the American Medical Association.

Treating abnormal retinal blood vessels with laser therapy became the standard treatment for proliferative diabetic retinopathy after the NEI announced results of the Diabetic Retinopathy Study in 1976. Although laser therapy effectively preserves central vision, it can damage night and side vision; so, researchers have sought therapies that work as well or better than laser but without such side effects.

A complication of diabetes, diabetic retinopathy can damage blood vessels in the light-sensitive retina in the back of the eye. As the disease worsens, blood vessels may swell, become distorted and lose their ability to function properly. Diabetic retinopathy becomes proliferative when lack of blood flow in the retina increases production of a substance called vascular endothelial growth factor, which can stimulate the growth of new, abnormal blood vessels. These new vessels are prone to bleeding into the center of the eye, often requiring a surgical procedure called a vitrectomy to clear the blood. The abnormal blood vessels can also cause scarring and retinal detachment. Lucentis is among several drugs that block the effects of vascular endothelial growth factor.

About 7.7 million U.S. residents have diabetic retinopathy, a leading cause of blindness among working-age Americans. Among these, about 1.5 percent have PDR.

The DRCR.net enrolled 305 participants (394 eyes) with proliferative diabetic retinopathy in one or both eyes at 55 clinical sites across the country. Eyes were assigned randomly to treatment with Lucentis or laser. For participants who enrolled both eyes in the study, one eye was assigned to the laser group and the other was assigned to the Lucentis group. About half of the eyes assigned to the laser group required more than one round of laser treatment. In the other group, Lucentis (0.5 mg/0.05 ml) was given via injections into the eye once per month for three consecutive months, and then as needed until the disease resolved or stabilized.

Because Lucentis is commonly used to treat diabetic macular edema—the build-up of fluid in the central area of the retina—the study permitted the use of Lucentis for diabetic macular edema in the laser group, if necessary. Slightly more than half (53 percent) of eyes in the laser group received Lucentis injections to treat diabetic macular edema. About 6 percent of eyes in the Lucentis group received laser therapy, mostly to treat retinal detachment or bleeding.

At two years, vision in the Lucentis group improved by about half a line on an eye chart compared with virtually no change in the laser group. There was little change in side vision with injection (average worsening of 23 decibels) but a substantial loss of side vision with laser (average worsening of 422 decibels).   The vitrectomy rate was lower in the Lucentis group (8 of 191 eyes) than in the laser group (30 of 203 eyes).

Rates of serious systemic adverse events, including cardiac arrest and stroke, were similar between the two groups. One patient in the Lucentis group developed endophthalmitis, an infection in the eye. Other side effects were low, with little difference between treatment groups.

“Lucentis should be considered a viable treatment option for people with proliferative diabetic retinopathy, especially for individuals needing anti-vascular endothelial growth factor for diabetic macular edema,” said Jeffrey G. Gross, M.D., of the Carolina Retina Center in Columbia, South Carolina, who chaired the study. Dr. Gross presented results November 13, 2015, at the annual meeting of the American Academy of Ophthalmology in Las Vegas.

In addition to treating proliferative diabetic retinopathy, the report suggests Lucentis may even help prevent diabetic macular edema from occurring. Among people without diabetic macular edema at the start of the study, only 9 percent of Lucentis-treated eyes developed diabetic macular edema during the study, compared with 28 percent in the laser group. The DRCR.net will continue to follow patients in this study for a total of five years.

The DRCR.net is dedicated to facilitating multicenter clinical research of diabetic eye disease. The network formed in 2002 and comprises more than 350 physicians practicing at more than 140 clinical sites across the country. For more information, visit the DRCR.net website at http://drcrnet.jaeb.org/(link is external).

The study was funded by NEI grants EY14231, EY23207, EY18817.

Lucentis was provided by Genentech. Additional research funding for this study was provided by the National Institute of Diabetes and Digestive and Kidney Diseases, also a part of the NIH.

The study is registered as NCT01489189 at ClinicalTrials.gov(link is external).

The NEI provides information about diabetic eye disease at http://www.nei.nih.gov/health/diabetic/.

Information about diabetes is available through the National Diabetes Education Program, www.ndep.nih.gov/.

View an NEI video about the study at https://youtu.be/jPoCIa0_1po(link is external).

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palivizumab prophylaxis for children with bronchiolitis

Larry H. Bernstein, MD, FCAP, Curator

LPBI

 

 

Eligibility for palivizumab prophylaxis in a cohort of children with severe bronchiolitis
Kohei Hasegawa,1 Jonathan M. Mansbach,2 Pedro A. Piedra,3 Michelle B. Dunn,4 Sunday Clark,5 Ashley F. Sullivan1 and Carlos A. Camargo Jr1

Pediatrics International (2015) 57, 1031–1034          http://dx.doi.org:/10.1111/ped.12760

 

In 2014, the American Academy of Pediatrics (AAP) updated their recommendations for palivizumab prophylaxis for children who are at high risk for severe respiratory syncytial virus (RSV) infection. To investigate the potential impact of the more restrictive 2014 criteria on the eligibility for palivizumab prophylaxis, we applied the 2012 and 2014 AAP recommendations for palivizumab prophylaxis to a multicenter cohort of 2207 US children hospitalized for bronchiolitis. According to the 2012 AAP recommendations, 215 children (9.7%) were eligible for palivizumab prophylaxis, while 140 children (6.3%) would have been eligible based on the 2014 updated recommendations (34.9% relative decrease; 95% CI: 28.5–41.7%).  The  decrease was largely driven by the restriction of eligibility to preterm infants with gestational age < 29weeks. Further development of and refinement of cost-effective approaches for the prevention of severe RSV infection are needed.

 

Bronchiolitis remains an important public health problem in the USA. It is the leading cause of hospitalization in infants, accounting for 18% of all infant hospitalizations, with a total direct cost of $545m in 2009.1 Although many viruses are known to cause bronchiolitis, respiratory syncytial virus (RSV) is the most common etiology among children requiring hospitalization.2 Palivizumab, a humanized monoclonal antibody against the RSV Fglycoprotein, is licensed for the prevention of serious lower respiratory infection caused by RSV in high-risk children. Since palivizumab was first licensed, professional organizations have sought more precise guidance for determining who is at high risk.3

In 2014, the American Academy of Pediatrics (AAP) updated and replaced their recommendations for palivizumab prophylaxis from 2012.4  The updated guidelines support a more restrictive use of palivizumab:3 for example, they recommend against the use in infants born ≥ 29 weeks’ gestation who have no additional risk factors for severe RSV disease. Despite these substantial changes to the guideline recommendations, there are no publications that assess the potential impact on the eligibility for palivizumab prophylaxis in US children.

To address the knowledge gap in the literature, we investigate the potential impact of the more restrictive 2014 criteria on the eligibility for palivizumab prophylaxis in a well-characterized national cohort of children hospitalized for bronchiolitis.

 

Over the 3year study period, we enrolled 2207 children hospitalized for bronchiolitis to one of the 16 sites. Demographic characteristics, medical history, and clinical course are summarized in Table 1. Overall, the median age was 4months (IQR, 2–9 months) and 1311 (59.4%) were male. Additionally, 285 children (12.9%) were born at gestational age <35 weeks; 460 (20.8%) had one or more major comorbid medical disorders.

Table 1 Bronchiolitis patient characteristics vs AAP palivizumab recommendations

Table 2 Eligibility for palivizumab prophylaxis vs 2012 and 2014 AAP recommendations

According to the 2012 AAP recommendations, 215 children (9.7%) were eligible for palivizumab prophylaxis (Table 2), while 140 children (6.3%) would have been eligible based on the 2014 updated recommendations. Applying the more restrictive 2014 criteria would have led to 75 fewer children (34.9% relative decrease; 95%CI: 28.5–41.7%) being eligible for palivizumab prophylaxis. The most frequent reason for the loss of eligibility was the 2014 criterion for prematurity that restricts eligibility to infantswithgestationalage<29weeks;thischangeledto45fewer children being eligible (40.9% relative decrease; 95%CI: 31.6–50.7%). The next most frequent reason was the 2014 criteria that limit eligibility to infants with chronic lung disease or congenital heart disease in the first year of life;this change led to 22 fewer children being eligible for palivizumab prophylaxis (22.9%relative decrease; 95%CI: 15.0–32.6%).

Among the 2207 children in the cohort, 207 children (9.4%) had received palivizumab prophylaxis prior to the index hospitalization. Among 215 children eligible for prophylaxis based on the 2012 recommendations, 117 (54.4%) had received palivizumab prophylaxis. Among 140 children eligible for prophylaxis based on the 2014 recommendations, 72 (51.4%) had received palivizumab prophylaxis (Table 1).

 

In this analysis of a large multicenter cohort of children hospitalized for bronchiolitis, we found that approximately 10% of children were eligible for palivizumab prophylaxis based on the 2012 AAP recommendations. When applying the more restrictive criteria of the 2014 updated recommendations, one-third of these children would have become ineligible for palivizumab prophylaxis. To thebestofourknowledge,thisisthe firststudytoreportthepotential impact of the change in the AAP recommendations on the eligibility for palivizumab prophylaxis in young children, a finding of public health and research importance.

In 1998, palivizumab was licensed by the US Food and Drug Administration (FDA) for prevention of severe RSV diseases in children at high risk, but the FDA did not issue more specific recommendations, nor define high risk.This absence of a specific definition has led several groups to attempt to identify children at high risk who would be eligible for palivizumab prophylaxis.3,6 The AAP published the first policy statement on the use of palivizumab in 1998.7 On the basis of the availability of additional data, the AAP has updated the guidelines in 2003, 2006, 2009, 2012,4 and 2014.3 Since the last update of the AAP recommendations, some studies have reported a high cost but limited benefit from palivizumab prophylaxis.8 In this context, the 2014 AAP guidelines recommended a more restrictive use.3 In particular, preterm infants with gestational age ≥29 weeks without additional risk factors became ineligible for palivizumab.

In parallel with this change in recommendations, within the present high risk population, the most frequent reason for the loss of eligibility was the use of the restrictive criterion for prematurity: that is, preterm infants born from 29t o35 weeks’ gestation with no additional risk factors became ineligible. This specific group of preterm infants accounts fo ra large number of births in the US:approximately 10% of US births in 2012.9 Thus, one may argue that the use of this restrictive criterion would result in an increase in the number of preventable severe RSV infections,10 even considering the potentially limited efficacy of palivizumab in this population. As described in the technical report of the 2014 AAP recommendations, however, it is challenging to define an optimal threshold of gestational age in preterm infants for which palivizumab prophylaxis may be indicated. The present observations should facilitate further investigations that seek high-quality and cost-effective preventive strategies for a large number of vulnerable children.

This study has several potential limitations. First, the analysis was not designed to examine the efficacy or effectiveness of palivizumabprophylaxis. Rather, we sought to examinethe potential impact of the updated recommendations on the eligibility for palivizumab in a well-characterized national cohort of children hospitalized for bronchiolitis. Second, the present study investigated only children hospitalized for bronchiolitis; thus, those with other types of severe respiratory infection (e.g. pneumonia) were not examined. Inclusion of these populations may yield different inferences. Nevertheless, the present findings are directly relevant to >120 000 US children hospitalized for bronchiolitis (and their families) each year.1 Finally, the study participants were those who were hospitalized in academic centers. Therefore, the present inferences may not be generalizable to the US population as a whole. Children hospitalized at academic centers, however, have disproportionately high morbidity; it is in precisely this population for which targeted preventive measures are needed.

In conclusion, we found that 10% of children hospitalized for bronchiolitis were eligible for palivizumab prophylaxis based on the 2012 AAP recommendations. When we applied the more restrictive 2014criteria,one-third of these children were ineligible. The decrease was largely driven by the restriction of eligibility to preterminfantswithgestationalage <29weeks.Forpolicymakers and researchers, because bronchiolitis continues to be a substantial societal burden in an already-stressed health-care system,1 the present findings support further development and refinement of cost effective approaches for the prevention of severe RSV infection.

 

References

1 Hasegawa K,Tsugawa Y,Brown DF,Mansbach JM,Camargo CA Jr. Trends in bronchiolitis hospitalizations in the United States, 2000–2009. Pediatrics 2013; 132: 28 –36.

2 Hasegawa K, Mansbach JM,Camargo CAJr.Infectious pathogens and bronchiolitis outcomes. Expert Rev. Anti Infect. Ther. 2014; 12: 817 –28.

3 American Academy of Pediatrics Committee on Infectious Diseases and Bronchiolitis Guidelines Committee. Policy statement. Updated guidance for palivizumab prophylaxis among infants and young children at increased risk of hospitalization for respiratory syncytial virus infection. Pediatrics 2014; 134: 415 –20.

4 American Academy of Pediatrics. Respiratory syncytial virus. In: Pickering LK, Baker CJ, Kimberlin DW, Long SS (eds). Red Book: 2012. Report of the Committee on Infectious Diseases. American Academy of Pediatrics, Elk Grove Village, IL, 2012; 609–18.

5 Hasegawa K, Jartti T, Mansbach JM etal.Respiratory syncytial virus genomic load and disease severity among children hospitalized with bronchiolitis: Multicenter cohort studies in the United States and Finland. J. Infect. Dis. 2015; 211: 1550 –9.

6 NHS Commissioning Board. Clinical Commissioning Policy: Palivizumab to reduce the risk of RSV in high risk infants. 2012. Accessed 13 May 2015. Available from URL: http://www.england.nhs.uk/.

7 American Academy of P

ediatrics Committee on Infectious Diseases and Committee of Fetus and Newborn. Prevention of respiratory syncytial virus infections: Indications for the use of palivizumab and update on the use of RSV-IGIV. Pediatrics 1998; 102: 1211 –6.

8 Andabaka T, Nickerson JW, Rojas-Reyes MX, Rueda JD,  Bacic Vrca V, Barsic B. Monoclonal antibody for reducing the risk of respiratory syncytial virus infection in children. Cochrane Database Syst. Rev. 2013; 4 CD 006602.

9 American Academy of Pediatrics Committee on Infectious Diseases and Bronchiolitis Guidelines Committee. Technical report. Updated guidance for palivizumab prophylaxis among infants and young children at increased risk of hospitalization for respiratory syncytial virus infection. Pediatrics 2014; 134 (2): e620–38.

Appendix I. Principal Investigators at the 16 participating sites in MARC-30
Besh Barcega, MD Loma Linda University Children’s Hospital, Loma Linda, CA, USA

John Cheng, MD Children’s Healthcare of Atlanta at Egleston, Atlanta, GA, USA

Carlos Delgado, MD Children’s Healthcare of Atlanta at Egleston, Atlanta, GA, USA

Haitham Haddad, MD Rainbow Babies and Children’s Hospital, Cleveland, OH, USA

Frank LoVecchio, MD Maricopa Medical Center, Phoenix, AZ, USA

Eugene Mowad, MD Akron Children’s Hospital, Akron, OH, USA

Brian Pate, MD Children’s Mercy Hospital and Clinics, Kansas City, MO, USA

Mark Riederer, MD Monroe Carell Jr. Children’s Hospital at Vanderbilt, Nashville, TN, USA

Paul Hain, MD Monroe Carell Jr. Children’s Hospital at Vanderbilt, Nashville, TN, USA M

Jason Sanders, MD Children’s Memorial Hermann Hospital, Houston, TX, USA

Nikhil Shah, MD New York Presbyterian Hospital, New York, NY, USA

Dorothy Damore, MD New York Presbyterian Hospital, New York, NY, USA

Michelle Stevenson, MD Kosair Children’s Hospital, Louisville, KY, USA

Erin Stucky Fisher, MD Rady Children’s Hospital, San Diego, CA, USA

Stephen Teach, MD, MPH Children’s National Medical Center, Washington, DC, USA

Lisa Zaoutis, MD Children’s Hospital of Philadelphia, Philadelphia, PA, USA

 

 

 

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Lymph2 Generation and regulation of anti-tumor immunity

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Monoclonal Antibody Therapy: What is in the name or clear description?

Curator: Demet Sag, PhD, CRA, GCP 

What is in the name?

Nomenclature is important part of the scientific community so we can stay on the same page in all kinds of communications for clarity. Therefore, a defined nomenclature scheme for assigning generic, or nonproprietary, names to monoclonal antibody drugs is used by the World Health Organization’s International Nonproprietary Names (INN) and the United States Adopted Names (USAN). In general, word stems are used to identify classes of drugs, in most cases placed at the end of the word.

Knowing what Antibody relies on understanding of immune response system so that one can modify the cells, choose correct biomarkers from the primary pathways (like Notch, WNT etc), know signaling from outside to inside (like GPCRs, MAPKs, nuclear transcription receptors), personalized gene make up (genomics) and key gene regulation mechanisms. Thus, immunomodulation can be done for immunotherapies. The admiration of these cells generate the new era called biosensors.

  • All monoclonal antibody names end with the stem -mab.
  • Unlike most other pharmaceuticals, monoclonal antibody nomenclature uses different preceding word parts (morphemes) depending on antibody structure and function. These are officially called sub-stemsand sometimes erroneously infixes.
  • This nomenclature is also used for fragments of monoclonal antibodies, such as antigen binding fragments and single-chain variable fragments.

The nomenclature has been updated. The main criteria is naming the origin, target, make up/type of antibody, ans of course suffix to show it is a monoclonal antibody.

Components

Substem for origin/source. 

The substem preceding the -mab suffix denotes the animal from which the antibody is obtained.

The first monoclonal antibodies were produced

  • in mice (substem -o-), yielding the ending -omab; usually Mus musculus, the house mouse),
  • primates (-i-), yielding -imab;
  • usually Macaca irus, the Crab-eating Macaque.

Need and RD:

There was a dis-advantage of using non-human Abs since they induce immune responses that are generating side effects, such as provoking allergy reactions, due to fast clearance from the body lost effectiveness etc.

As a result, new types of monoclonal antibodies were engineered developed to avoid negative impacts.

Mainly placing human origin sequences:

  • Chimeric, the constant region is replaced with the human form so the substem used is -xi-., in which case it is called
  • Humanized, Part of the variable regions, typically everything but the complementarity determining regions, may also be substituted, so substem used is -zu-.
  • Partly chimeric and partly humanized antibodies use -xizu-.

*These three substems do not indicate the foreign species used for production.

Thus,

  • the human/mouse chimeric antibody ba-s-il-i-ximab ends in -ximab
  • the human/macaque antibody go-m-il-i-ximab ends in -ximab.
  • Pure human antibodies use -u-.

Rat/mouse hybrid antibodies:

  • They can be engineered with binding sites for two different antigens.
  • These drugs, termed trifunctional antibodies, have the substem -axo.

Substem for target
The substem preceding the source of the antibody refers to the medicine’s target.

Examples of targets are:

  • tumors,
  • organ systems like the circulatory system, or
  • Infectious agents like bacteria or viruses.

However;

  • The term targetdoes not imply what sort of action the antibody exerts.
  • Therapeutic, prophylactic and diagnostic agents are not distinguished by this nomenclature.

In the naming scheme as originally developed, these substems mostly consist of a consonant, a vowel, then another consonant. For ease of pronunciation and to avoid awkwardness, the final consonant may be dropped if the following source substem begins with a consonant (such as -zu- or -xi-).

Examples of these include:

  • -ci(r)- for the circulatory system,
  • -li(m)-for the immune system (limstands for lymphocyte) and
  • -ne(r)-or -neu(r)- for the nervous system.

This results in endings like –li-mu-mab (immune system, human) or –ci-ximab (circulatory system, chimeric, consonant dropped).

In 2009, new and shorter target substems were introduced.

They mostly consist of a consonant, plus a vowel which is omitted if the source substem begins with a consonant.

For example, human antibodies targeting the immune system receive names ending in -lumab instead of the old -limumab. Some endings like -ciximab remain unchanged.

Prefix
The prefix carries no special meaning and should be unique for each medicine.

Additional words
A second word may be added if there is another substance attached or linked. If the drug contains a radioisotope, the name of the isotope precedes the name of the antibody.

 

Examples

New convention

  • Olara-t-u-mab
  • is an antineoplastic. Its name is composed of olara- + -t- + -u- + -mab.
  • shows that the drug is a human monoclonal antibody acting against tumors.
  • Benra-li-zu-mab
  • a drug designed for the treatment of asthma,
  • benra--li- + -zu- + -mab, marking it as a humanized antibody acting on the immune system.

http://www.nature.com/polopoly_fs/7.10768.1369754844!/image/ASCO-cancer-graph.jpg_gen/derivatives/fullsize/ASCO-cancer-graph.jpg

Example FDA approved therapeutic monoclonal antibodies[1]
Antibody Brand name Company Approval date Type Target Indication
(Targeted disease)
Abciximab ReoPro Eli Lilly 1994 chimeric inhibition of glycoprotein IIb/IIIa Cardiovascular disease
Adalimumab Humira Abbott Laboratories 2002 human inhibition of TNF-α signaling Several auto-immune disorders
Alemtuzumab Campath Genzyme 2001 humanized CD52 Chronic lymphocytic leukemia
Basiliximab Simulect Novartis 1998 chimeric IL-2Rα receptor (CD25) Transplant rejection
Belimumab Benlysta GlaxoSmithKline 2011 human inihibition of B- cell activating factor Systemic lupus erythematosus
Bevacizumab Avastin Genentech/Roche 2004 humanized Vascular endothelial growth factor (VEGF) Colorectal cancerAge related macular degeneration (off-label)
Brentuximab vedotin Adcetris 2011 Chimeric CD30 Anaplastic large cell lymphoma (ALCL) andHodgkin lymphoma
Canakinumab Ilaris Novartis 2009 Human IL-1β Cryopyrin-associated periodic syndrome(CAPS)
Cetuximab Erbitux Bristol-Myers Squibb/Eli Lilly/Merck KGaA 2004 chimeric epidermal growth factor receptor Colorectal cancerHead and neck cancer
Certolizumab pegol[23] Cimzia UCB (company) 2008 humanized inhibition of TNF-α signaling Crohn’s disease
Daclizumab Zenapax Genentech/Roche 1997 humanized IL-2Rα receptor (CD25) Transplant rejection
Denosumab Prolia, Xgeva Amgen 2010 Human RANK Ligand inhibitor Postmenopausal osteoporosis, Solid tumor`s bony metasteses
Eculizumab Soliris Alexion Pharmaceuticals 2007 humanized Complement system protein C5 Paroxysmal nocturnal hemoglobinuria
Efalizumab Raptiva Genentech/Merck Serono 2002 humanized CD11a Psoriasis
Golimumab Simponi Johnson & Johnson/Merck & Co, Inc. 2009 Human TNF-alpha inihibitor Rheumatoid arthritisPsoriatic arthritis, andAnkylosing spondylitis
Ibritumomab tiuxetan Zevalin Spectrum Pharmaceuticals, Inc. 2002 murine CD20 Non-Hodgkin lymphoma (with yttrium-90 orindium-111)
Infliximab Remicade Janssen Biotech, Inc./Merck & Co 1998 chimeric inhibition of TNF-α signaling Several autoimmune disorders
Ipilimumab ( MDX-101 ) Yervoy 2011 Human blocks CTLA-4 Melanoma
Muromonab-CD3 Orthoclone OKT3 Janssen-Cilag 1986 murine T cell CD3 Receptor Transplant rejection
Natalizumab Tysabri Biogen Idec/Élan 2006 humanized alpha-4 (α4) integrin, Multiple sclerosis and Crohn’s disease
Nivolumab Obdivo 2014 Human blocks PD-1 Melanoma and SCC
Ofatumumab Arzerra 2009 Human CD20 Chronic lymphocytic leukemia
Omalizumab Xolair Genentech/Novartis 2004 humanized immunoglobulin E (IgE) mainly allergy-related asthma
Palivizumab Synagis MedImmune 1998 humanized an epitope of the RSV F protein Respiratory Syncytial Virus
Panitumumab Vectibix Amgen 2006 human epidermal growth factor receptor Colorectal cancer
Ranibizumab Lucentis Genentech/Novartis 2006 humanized Vascular endothelial growth factor A (VEGF-A) Macular degeneration
Rituximab Rituxan, Mabthera Biogen Idec/Genentech 1997 chimeric CD20 Non-Hodgkin lymphoma
Tocilizumab ( or Atlizumab ) Actemra and RoActemra 2010 Humanised Anti- IL-6R Rheumatoid arthritis
Tositumomab Bexxar GlaxoSmithKline 2003 murine CD20 Non-Hodgkin lymphoma
Trastuzumab Herceptin Genentech 1998 humanized ErbB2 Breast cancer
Ustekinumab Stelara Centocor 2013 IL-12 , IL-23 Psoriatic Arthritis, Plaque Psoriasis
Vedolizumab Entyvio Takeda 2014 humanized integrin α4β7 Crohn’s diseaseulcerative colitis

Recently, the bispecific antibodies, a novel class of therapeutic antibodies, have yielded promising results in clinical trials. In April 2009, the bispecific antibody catumaxomab was approved in the European Union.

References:

Wolchok JD, Chan TA. Cancer: Antitumour immunity gets a boost. Nature. 2014Nov 27;515(7528):496-8. doi: 10.1038/515496a. PubMed PMID: 25428495.

 

Hoag H. Drug development: a chance of survival. Nature. 2014 Nov 20;515(7527):S118-20. doi: 10.1038/515S118a. PubMed PMID: 25407709.

 

Ledford H. Cancer treatment: The killer within. Nature. 2014 Apr 3;508(7494):24-6. doi: 10.1038/508024a. PubMed PMID: 24695297.

 

Weintraub K. Drug development: Releasing the brakes. Nature. 2013 Dec 19;504(7480):S6-8. doi: 10.1038/504S6a. PubMed PMID: 24352363.

 

Elert E. Calling cells to arms. Nature. 2013 Dec 19;504(7480):S2-3. doi: 10.1038/504S2a. PubMed PMID: 24352361.

 

Mellman I, Coukos G, Dranoff G. Cancer immunotherapy comes of age. Nature. 2011 Dec 21;480(7378):480-9. doi: 10.1038/nature10673. Review. PubMed PMID: 22193102; PubMed Central PMCID: PMC3967235.

 

Dolgin E. FDA narrows drug label usage. Nature. 2009 Aug 27;460(7259):1069. doi: 10.1038/4601069a. PubMed PMID: 19713906.

 

Ellis LM, Reardon DA. Cancer: The nuances of therapy.  Nature. 2009 Mar 19;458(7236):290-2. doi: 10.1038/458290a. PubMed PMID: 19295595.

 

Izumi Y, Xu L, di Tomaso E, Fukumura D, Jain RK. Tumour biology: herceptin acts as an anti-angiogenic cocktail.  Nature. 2002 Mar 21;416(6878):279-80. PubMed PMID: 11907566.

 

Kim KJ, Li B, Winer J, Armanini M, Gillett N, Phillips HS, Ferrara N. Inhibition of vascular endothelial growth factor-induced angiogenesis suppresses tumour growth in vivo. Nature. 1993 Apr 29;362(6423):841-4. PubMed PMID: 7683111.

 

Sredni B, Caspi RR, Klein A, Kalechman Y, Danziger Y, Ben Ya’akov M, Tamari T, Shalit F, Albeck M. A new immunomodulating compound (AS-101) with potential therapeutic application.  Nature. 1987 Nov 12-18;330(6144):173-6. PubMed PMID: 3118216.

 

Cobbold SP, Waldmann H. Therapeutic potential of monovalent monoclonal antibodies.

Nature. 1984 Mar 29-Apr 4;308(5958):460-2. PubMed PMID: 6608694.

 

Shouval D, Shafritz DA, Zurawski VR Jr, Isselbacher KJ, Wands JR. Immunotherapy in nude mice of human hepatoma using monoclonal antibodies against hepatitis B virus. Nature. 1982 Aug 5;298(5874):567-9. PubMed PMID: 7099252.

 

Thorpe PE, Mason DW, Brown AN, Simmonds SJ, Ross WC, Cumber AJ, Forrester JA. Selective killing of malignant cells in a leukaemic rat bone marrow using an antibody-ricin conjugate. Nature. 1982 Jun 17;297(5867):594-6. PubMed PMID:7088145.

 

Beverley PC. Antibodies and cancer therapy. Nature. 1982 Jun 3;297(5865):358-9. PubMed PMID: 7078646.

 

Trowbridge IS. Cancer monoclonals.  Nature. 1981 Nov 19;294(5838):204. PubMed PMID: 7300906.

 

Blythman HE, Casellas P, Gros O, Gros P, Jansen FK, Paolucci F, Pau B, Vidal Immunotoxins: hybrid molecules ofmonoclonal antibodiesand a toxin subunit specifically kill tumour cells.  Nature. 1981 Mar 12;290(5802):145-6. PubMed PMID:  7207595.

 

Selected FDA Approved Mab Drugs:

(John, Martin et al. 2005, Robert, Ann et al. 2006, Albert, Edvardas et al. 2012, Claro, Karen et al. 2012, Gideon, Nancy et al. 2013, Michael, Ke et al. 2013, Thomas, Albert et al. 2013, Hyon-Zu, Barry et al. 2014, Larkins, Scepura et al. 2015, Sandra, Ibilola et al. 2015, Sean, Gideon et al. 2015)

Albert, D., K. Edvardas, G. Joseph, C. Wei, S. Haleh, L. L. Hong, D. R. Mark, B. Satjit, W. Jian, G. Christine, B. Julie, B. B. Laurie, R. Atiqur, S. Rajeshwari, F. Ann and P. Richard (2012). “U.S. Food and Drug Administration Approval: Ruxolitinib for the Treatment of Patients with Intermediate and High-Risk Myelofibrosis.” Clinical Cancer Research: 3212-3217.

Claro, R. A. d., M. Karen, K. Virginia, B. Julie, K. Aakanksha, H. Bahru, O. Yanli, S. Haleh, L. Kyung, K. Kallappa, R. Mark, S. Marjorie, B. Francisco, C. Kathleen, C. Xiao Hong, B. Janice, A. Lara, K. Robert, K. Edvardas, F. Ann and P. Richard (2012). “U.S. Food and Drug Administration Approval Summary: Brentuximab Vedotin for the Treatment of Relapsed Hodgkin Lymphoma or Relapsed Systemic Anaplastic Large-Cell Lymphoma.” Clinical Cancer Research: 5845-5849.

Gideon, M. B., S. S. Nancy, C. Patricia, C. Somesh, T. Shenghui, S. Pengfei, L. Qi, R. Kimberly, M. P. Anne, T. Amy, E. K. Kathryn, G. Laurie, L. R. Barbara, C. W. Wendy, C. Bo, T. Colleen, H. Patricia, I. Amna, J. Robert and P. Richard (2013). “First FDA approval of dual anti-HER2 regimen: pertuzumab in combination with trastuzumab and docetaxel for HER2-positive metastatic breast cancer.” Clinical cancer research : an official journal of the American Association for Cancer Research: 4911-4916.

Hyon-Zu, L., W. M. Barry, E. K. Virginia, R. Stacey, D. Pedro, S. Haleh, G. Joseph, B. Julie, F. Jeffry, M. Nitin, K. Chia-Wen, N. Lei, S. Marjorie, T. Mate, C. K. Robert, K. Edvardas, J. Robert, T. F. Ann and P. Richard (2014). “U.S. Food and drug administration approval: obinutuzumab in combination with chlorambucil for the treatment of previously untreated chronic lymphocytic leukemia.” Clinical cancer research : an official journal of the American Association for Cancer Research: 3902-3907.

John, R. J., C. Martin, S. Rajeshwari, C. Yeh-Fong, M. W. Gene, D. John, G. Jogarao, B. Brian, B. Kimberly, L. John, H. Li Shan, C. Nallalerumal, Z. Paul and P. Richard (2005). “Approval Summary for Erlotinib for Treatment of Patients with Locally Advanced or Metastatic Non–Small Cell Lung Cancer after Failure of at Least One Prior Chemotherapy Regimen.” Clinical Cancer Research 11(18).

Larkins, E., B. Scepura, G. M. Blumenthal, E. Bloomquist, S. Tang, M. Biable, P. Kluetz, P. Keegan and R. Pazdur (2015). “U.S. Food and Drug Administration Approval Summary: Ramucirumab for the Treatment of Metastatic Non-Small Cell Lung Cancer Following Disease Progression On or After Platinum-Based Chemotherapy.” The oncologist.

Michael, A., L. Ke, J. Xiaoping, H. Kun, W. Jian, Z. Hong, K. Dubravka, P. Todd, D. Zedong, R. Anne Marie, M. Sarah, K. Patricia and P. Richard (2013). “U.S. Food and Drug Administration approval: vismodegib for recurrent, locally advanced, or metastatic basal cell carcinoma.” Clinical cancer research : an official journal of the American Association for Cancer Research: 2289-2293.

Robert, C. K., T. F. Ann, S. Rajeshwari and P. Richard (2006). “United States Food and Drug Administration approval summary: bortezomib for the treatment of progressive multiple myeloma after one prior therapy.” Clinical cancer research : an official journal of the American Association for Cancer Research: 2955-2960.

Sandra, J. C., F.-A. Ibilola, J. L. Steven, Z. Lillian, J. Runyan, L. Hongshan, Z. Liang, Z. Hong, Z. Hui, C. Huanyu, H. Kun, D. Michele, N. Rachel, K. Sarah, K. Sachia, H. Whitney, K. Patricia and P. Richard (2015). “FDA Approval Summary: Ramucirumab for Gastric Cancer.” Clinical cancer research : an official journal of the American Association for Cancer Research: 3372-3376.

Sean, K., M. B. Gideon, Z. Lijun, T. Shenghui, B. Margaret, F. Emily, H. Whitney, L. Ruby, S. Pengfei, P. Yuzhuo, L. Qi, Z. Ping, Z. Hong, L. Donghao, T. Zhe, H. Ali Al, B. Karen, K. Patricia, J. Robert and P. Richard (2015). “FDA approval: ceritinib for the treatment of metastatic anaplastic lymphoma kinase-positive non-small cell lung cancer.” Clinical cancer research : an official journal of the American Association for Cancer Research: 2436-2439.

Thomas, M. H., D. Albert, K. Edvardas, C. K. Robert, M. K. Kallappa, D. R. Mark, H. Bahru, B. Julie, D. B. Jeffrey, H. Jessica, R. P. Todd, J. Josephine, A. William, M. Houda, B. Janice, D. Angelica, S. Rajeshwari, T. F. Ann and P. Richard (2013). “U.S. Food and Drug Administration Approval: Carfilzomib for the Treatment of Multiple Myeloma.” Clinical Cancer Research: 4559-4563.

Further Reading:

Waldmann, Thomas A. (2003). “Immunotherapy: past, present and future”. Nature Medicine 9 (3): 269–277. doi:10.1038/nm0303-269. PMID 12612576.

Sharma, Pamanee; Allison, James P. (April 3, 2015). “The future of immune checkpoint therapy”. Science. doi:10.1126/science.aaa8172. Retrieved June 2015.

Gene Garrard Olinger, Jr., James Pettitt, Do Kim, Cara Working, Ognian Bohorov, Barry Bratcher, Ernie Hiatt, Steven D. Hume, Ashley K. Johnson, Josh Morton, Michael Pauly, Kevin J. Whaley, Calli M. Lear, Julia E. Biggins, Corinne Scully, Lisa Hensley, and Larry Zeitlin (2012). “Delayed treatment of Ebola virus infection with plant-derived monoclonal antibodies provides protection in rhesus macaques”. PNAS 109 (44): 18030–5.doi:10.1073/pnas.1213709109. PMC 3497800. PMID 23071322.

Janeway, Charles; Paul Travers; Mark Walport; Mark Shlomchik (2001).Immunobiology; Fifth Edition. New York and London: Garland Science. ISBN 0-8153-4101-6.

Janeway CA, Jr.; et al. (2005). Immunobiology. (6th ed.). Garland Science. ISBN 0-443-07310-4.

Modified from Carter P (November 2001). “Improving the efficacy of antibody-based cancer therapies”. Nat. Rev. Cancer 1 (2): 118–29. doi:10.1038/35101072.PMID 11905803.

Prof FC Breedveld (2000). “Therapeutic monoclonal antibodies”. Lancet.doi:10.1016/S0140-6736(00)01034-5.

Köhler G, Milstein C (August 1975). “Continuous cultures of fused cells secreting antibody of predefined specificity”. Nature 256 (5517): 495–7.Bibcode:1975Natur.256..495K. doi:10.1038/256495a0. PMID 1172191.

Nadler LM, Stashenko P, Hardy R, et al. (September 1980). “Serotherapy of a patient with a monoclonal antibody directed against a human lymphoma-associated antigen”.Cancer Res. 40 (9): 3147–54. PMID 7427932.

Stern M, Herrmann R (April 2005). “Overview of monoclonal antibodies in cancer therapy: present and promise”. Crit. Rev. Oncol. Hematol. 54 (1): 11–29.doi:10.1016/j.critrevonc.2004.10.011. PMID 15780905.

Carter P, Presta L, Gorman CM, et al. (May 1992). “Humanization of an anti-p185HER2 antibody for human cancer therapy”. Proc. Natl. Acad. Sci. U.S.A. 89 (10): 4285–9.Bibcode:1992PNAS…89.4285C. doi:10.1073/pnas.89.10.4285. PMC 49066.PMID 1350088.

Presta LG, Lahr SJ, Shields RL, et al. (September 1993). “Humanization of an antibody directed against IgE”. J. Immunol. 151 (5): 2623–32. PMID 8360482.

Jefferis, Roy; Marie-Paule Lefranc (July–August 2009). “Human immunoglobulin allotypes”. MAbs 1 (4): 332–338. doi:10.4161/mabs.1.4.9122. PMC 2726606.PMID 20073133.

Chapman, Kathryn; Nick Pullen, Lee Coney, Maggie Dempster, Laura Andrews, Jeffrey Bajramovic, Paul Baldrick, Lorrene Buckley, Abby Jacobs, Geoff Hale, Colin Green, Ian Ragan and Vicky Robinson (2009). “Preclinical development of monoclonal antibodies”.MAbs 1 (5): 505–516. doi:10.4161/mabs.1.5.9676. PMC 2759500. PMID 20065651.

Rang, H. P. (2003). Pharmacology. Edinburgh: Churchill Livingstone. p. 241. ISBN 0-443-07145-4.

Hooks MA, Wade CS, Millikan WJ (1991). “Muromonab CD-3: a review of its pharmacology, pharmacokinetics, and clinical use in transplantation”. Pharmacotherapy 11(1): 26–37. PMID 1902291.

Goel, Niti; Stephens, Sue (2010). “Certolizumab Pegol”. MAbs 2 (2): 137–147.doi:10.4161/mabs.2.2.11271. PMC 2840232. PMID 20190560.

Chames, Patrick; Baty, Daniel (2009). “Bispecific antibodies for cancer therapy: The light at the end of the tunnel?”. MAbs 1 (6): 539–547. doi:10.4161/mabs.1.6.10015.PMC 2791310. PMID 20073127.

Linke, Rolf; Klein, Anke; Seimetz, Diane (2010). “Catumaxomab: Clinical development and future directions”. MAbs 2 (2): 129–136. doi:10.4161/mabs.2.2.11221.

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Larry H Bernstein, MD, FCAP, Reporter and curator

αllbβ3 Antagonists As An Example of Translational Medicine Therapeutics

http://phrmaceuticalintelligence.com/2013-10-12/larryhbern_BS-Coller/αllbβ3 Antagonists As An Example of Translational Medicine Therapeutics

by Barry S. Coller, MD
Rockefeller University

Introduction

This article is a segment in several articles about platelets, platelet function, and advances in applying the surge of knowledge to therapy.  In acute coronary syndromes, plaque rupture leads to thrombotic occlusion.  We have also seen that the development of a plaque occurs in 3 stages, only the last of which involves plaque rupture.  Platelets interact with the vascular endothelium, and platelet-endothelial as well as platelet-platelet interactions are known to be important in atherogenesis.  We learned that platelets are derived from megakaryocytes that break up and these elements are released into the blood stream.  It has recently been discovered that platelets can replicate in the circulation.  The turnover of platelets is rapid, and platelets sre stored at room temperature with shaking, and are viable for perhaps only 3-4 days once they are received in the blood bank for use.  In cardiology, the identification, isolation, and characterization of GPIIb/IIIa from the platelet was a huge advance in the potential for coronary intervention, and that potential became of paramount importance with the introduction of GPIIb/IIIa inhibitors as a standard in coronary vascular therapeutic procedures.   The following manuscript by Barry Coller, at Rockefeller University,  is a presentation of the GPIIb/IIIa story as an excellent example of Translational Medicine.

Search for GPIIb/IIIa inhibitor of the (anti-αIIb133 (GPIIb/IIIa) receptor)

The deliberate search for drugs to inhibit the αIIb133 (GPIIb/IIIa) receptor ushered in the era of rationally designed antiplatelet therapy and thus represents an important milestone in the evolution of antiplatelet drug development. The selection of the αIIb133 receptor as a therapeutic target rested on a broad base of basic and clinical research conducted by many investigators in the 1960s and 1970s working in the fields of platelet physiology, the rare bleeding disorder Glanzmann thrombasthenia, platelet membrane glycoproteins, integrin receptors, coronary artery pathology, and experimental thrombosis. Thus, αIIb133 was found to mediate platelet aggregation by virtually all of the physiology agonists (e.g., ADP, epinephrine, and thrombin) through a mechanism in which platelet activation by these agents results in a change in the conformation of the receptor. This is followed by increased affinity of the receptor for the multivalent ligands fibrinogen and von Willebrand factor, both of which are capable of binding to receptors on two platelets simultaneously, producing platelet crosslinking and aggregation. At about the same time, experimental studies demonstrated platelet thrombus formation at sites of vascular injury, and biochemical studies in humans demonstrated evidence of platelet activation during acute ischemic cardiovascular events.

Our own studies initially focused on platelet-fibrinogen interactions using an assay in which normal platelets agglutinated fibrinogen-coated beads. The agglutination was enhanced with platelet activators. Platelets from patients with Glanzmann thrombasthenia, who lack the αIIb133 receptor, did not agglutinate the beads. We adapted this assay to a microtiter plate system to identify monoclonal antibodies that inhibited platelet-fibrinogen interactions and then demonstrated that these antibodies bound to αIIb133. They were also more potent inhibitors of platelet aggregation than any known antiplatelet agent and produced a pattern of aggregation that was virtually identical to that found using platelets from patients with Glanzmann thrombasthenia.

I recognized the theoretical potential of using an antibody to inhibit platelets in vivo but also recognized the challenges and limitations. Since experimental models of thrombosis had been developed in the dog, and since the antibody we initially worked with did not react with dog platelets, we had to go back to our original samples to identify an antibody (7E3) that reacted with dog platelets in addition to human platelets. Since coating platelets with immunoglobulins results in their rapid elimination of the platelets from the circulation, and since the clearance is mediated by the immunoglobulin Fc region, we prepared F(ab’)2 fragments of 7E3 for our in vivo studies. Additional challenges included preparing large quantities of antibody on a very limited budget and purifying the antibodies so they contained only minimal amounts of endotoxin. With the small amount of 7E3-F(ab’)2 we initially prepared, we were able to show dose response inhibition of platelet aggregation in three dogs, achieving greater inhibition than with aspirin or ticlopidine, the only antiplatelet agents approved for human use at that time. We also devised an assay using radiolabeled 7E3 to quantify the percentage of platelet αIIbβ3 receptors that were blocked when a specific dose of 7E3-F(ab’)2 was administered in vivo. This allowed us to directly measure the effect of the agent on its target receptor on its target cell.

I considered two criteria most important in selecting the initial animal models in which to test the efficacy and safety of administering 7E3-F(ab’)2:

  • 1) the model had to convincingly simulate a human vascular disease, and
  • 2) aspirin had to have failed to produce complete protection from thrombosis.

The latter criterion was particularly important because I planned to stop this line of research if the 7E3-F(ab’)2 was not more efficacious than aspirin.

Ultimately, we collaborated with Dr. John Folts of the University of Wisconsin, who had developed a dog model of unstable angina by attaching a short cylindrical ring to partially occlude a coronary artery and using a hemostat to induce vascular injury. Pretreatment of the animal with 7E3-F(ab’)2 was more effective than aspirin or any other compound Dr. Folts had previously tested in preventing platelet thrombus formation, as judged by its effects on the characteristic repetitive cycles of platelet deposition and embolization. Electron microscopy of the vessels confirmed the reduction in platelet thrombi by 7E3-F(ab’)2, with only a monolayer of platelets typically deposited.

Dr. Chip Gold and his colleagues at Massachusetts General Hospital had developed a dog model to assess the effects of tissue plasminogen activator (t-PA) on experimental thrombi induced in the dog coronary artery. Although t-PA was effective in lysing the thrombi, the blood vessels rapidly reoccluded with new thrombi that were rich in platelets. Aspirin could not prevent reocclusion, whereas 7E3-F(ab’)2 not only prevented reocclusion, but also increased the speed of reperfusion by t-PA.

The next steps in drug development could not be performed in my laboratory because they required resources far in excess of those in my grant from the National Heart, Lung, and Blood Institute to study basic platelet physiology. As a result, in 1986 the Research Foundation of the State University of New York licensed the 7E3 antibody to Centocor, Inc., a new biotechnology company specializing in the diagnostic and therapeutic application of monoclonal antibodies.

Subsequent Development of 7E3

The subsequent development of 7E3 as a therapeutic agent required extensive collaboration among myself, a large number of outstanding scientists at Centocor, and many leading academic cardiologists. Many decisions and hurdles remained for us, including the decision to develop a mouse/human chimeric 7E3 Fab (c7E3 Fab); the design and execution of the toxicology studies; the assessment of the potential toxicity of 7E3 crossreactivity with αVβ3; the development of sensitive and specific assays to assess immune responses to c7E3 Fab; the design, execution, and analysis of the Phase I, II, and III studies; and the preparation, submission, and presentation of the Product Licensing  Application to the Food and Drug Administration, and comparable documents to European and Scandinavian agencies.

Based on the results of the 2,099 patient EPIC trial, in which conjunctive treatment with a bolus plus infusion of c7E3 Fab significantly reduced the risk of developing an ischemic complication (death, myocardial infarction, or need for urgent intervention) after coronary artery angioplasty or atherectomy in patients at high risk of such complications, the Food and Drug Administration approved the conjunctive use of c7E3 Fab (generic name, abciximab) in high-risk angioplasty and atherectomy on December 22, 1994. Since then it has been administered to more than 2.5 million patients in the U.S., Europe, Scandinavia, and Asia. Its optimal role in treating cardiovascular disease continues to evolve in response to the introduction of new anticoagulants, antiplatelet agents, stents, and procedures.

Extended Investigations

We have also been able to apply the monoclonal antibodies we prepared to αIIb33 to the prenatal detection of Glanzmann thrombasthenia, and have used the antibodies as probes for characterizing both the biogenesis of the receptor and the conformational changes that the receptor undergoes with activation. We have been able to precisely map the 7E3 epitope on 33, providing additional insights into the mechanism by which it prevents ligand binding. We have also exploited the ability of another antibody to αIIb33 to stabilize the receptor complex in order to facilitate production of crystals of the αIIb33 headpiece; the x-ray diffraction properties of these crystals were studied in collaboration with Dr. Timothy Springer’s group at Harvard and provide the first structural information on the receptor.

In landmark studies in the 1980s, Pierschbacher and Ruoslahti demonstrated the importance of the arginine-aspartic acid (RGD) sequence in the interaction of the integrin α531 with fibronectin, and they went on to show that peptides with the RGD sequence could inhibit this interaction. Subsequent studies by many groups demonstrated that these peptides could also inhibit the interaction of platelet αIIb33 with fibrinogen and von Willebrand factor. Dr. David Phillip and Dr. Robert Scarbrough led the team at Cor Therapeutics that made a cyclic pentapeptide with high selectivity for αIIb33 over αV33 by patterning their compound on the KGD sequence in the snake venom barbourin. The resulting antiplatelet agent, eptifibatide, received FDA approval in May 1998. At Merck, Dr. Robert Gould led the team that developed the nonpeptide RGD-mimetic tirofiban, which also is selective for αIIb33 compared to αV33. It also received FDA approval in May 1998. Our recent x-ray crystallographic studies in collaboration with Dr. Springer’s group provided structural information on the mechanisms and sites of binding of these drugs with αIIb33.

Translation of Basic Science into Therapy

Many important elements and an enormous amount of good fortune were needed for the translation of the basic science information about platelet aggregation into the drug abciximab, including, but not limited to:

  • 1) the support of basic studies of platelet physiology by the National Institutes of Health in my laboratory and many other laboratories,
  • 2) the creation and ongoing funding of a core facility available to all faculty members to prepare monoclonal antibodies at the State University of New York at Stony Brook under the direction of Dr. Arnold Levine,
  • 3) the 1988 Bayh-Dole Act and its subsequent amendments, and the expertise of the Technology Transfer Office at Stony Brook in licensing 7E3 to Centocor, which then provided the capital and additional expertise required for its development, and
  • 4) the expert and enthusiastic collaboration by two large and disciplined cooperative groups of interventional cardiologists (TAMI, EPIC) under the dynamic leadership of Drs. Eric Topol and Rob Califf,

tirofiban, that were eager to test the safety and efficacy of the 7E3 derivatives. Although the translation of each new scientific discovery into improved health via novel preventive, diagnostic, or therapeutic strategies requires the blazing of a unique path, optimizing these elements and similar ones may allow the path to be shorter and/or to be traversed more easily, at a lower cost, or in a shorter period of time.

 

Related articles in Pharmaceutical Intelligence:

Platelets in Translational Research – 1   Larry H. Bernstein, MD, FCAP
https://pharmaceuticalintelligence.com/10-6-2013/larryhbern/Platelets_in_Translational_Research-1
Platelets in Translational Research – 2  Larry H. Bernstein, MD, FCAP
http://phramaceuticalintelligence.com/2013-10-7/larryhbern/Platelets-in-Translational-Research-2/

Do Novel Anticoagulants Affect the PT/INR? The Cases of XARELTO (rivaroxaban) and PRADAXA (dabigatran)
Vivek Lal, MBBS, MD, FCIR, Justin D Pearlman, MD, PhD, FACC and Aviva Lev-Ari, PhD, RN
https://pharmaceuticalintelligence.com/2013/09/23/do-novel-anticoagulants-affect-the-ptinr-the-cases-of-xarelto-rivaroxaban-and-pradaxa-dabigatran/

 

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CD47: Target Therapy for Cancer

Author/Curator: Tilda Barliya

“A research team from Stanford University’s School of Medicine is now one step closer to uncovering a cancer treatment that could be applicable across the board in killing every kind of cancer tumor” (1). It appeared that their antibody-drug against the CD47 protein, enabled the shrinking of all tumor cells. After completing their animal studies the researchers now move into a human phase clinical trials. CD47 has been previously studied and evaluated for its role in multiple cells, some of this data however, is somewhat controversy. So where do we stand?

CD47

CD47 (originally named integrin-associated protein (IAP)) is a cell surface protein of the immunoglobulin (Ig) superfamily, which is heavily glycosylated and expressed by virtually all cells in the body and overexpressed in many types of cancer  including breast, ovarian, colon, prostate and others (3). CD47 was first recognized as a 50 kDa protein associated and copurified with the  Alpha-v-Beta-3 integrin in placenta and neutrophil granulocytes and later shown to have the capacity to regulate integrin function and the responsiveness of leukocytes to RGD-containing extracellular matrix proteins. CD47 has also been shown to be identical to the OA-3/OVTL3 antigen highly expressed on most ovarian carcinomas (4,5).

CD47 consists of an extracellular IgV domain, a five times transmembrane-spanning domain, and a short alternatively spliced cytoplasmic tail. In both humans and mice, the cytoplasmic tail can be found as four different splice isoforms ranging from 4 to 36 amino acids, showing different tissue expression patterns (3).

CD47 interactions (3, 6):

  • Thrombospondin-1 (TSP-1) – a secreted glycoprotein that plays a role in vascular development and angiogenesis. Binding of TSP-1 to CD47 influences several fundamental cellular functions including cell migration and adhesion, cell proliferation or apoptosis, and plays a role in the regulation of angiogenesis and inflammation.
  • Signal-regulatory protein-alpha (SIRPα) – an inhibitory transmembrane receptor present on myeloid cells. The CD47/SIRPα interaction leads to bidirectional signaling, resulting in different cell-to-cell responses including inhibition of phagocytosis, stimulation of cell-cell fusion, and T-cell activation.
  • Integrins – several membrane integrins, most commonly integrin avb3. These interactions result in CD47/integrin complexes that effect a range of cell functions including adhesion, spreading and migration

These interactions with multiple proteins and cells types create several important functions, which include:

  • Cell proliferation – cell proliferation is heavily dependent on cell type as both activation and loss of CD47 can result in enhanced proliferation. For example, activation of CD47 with TSP-1 in wild-type cells inhibits proliferation and reduces expression of stem cell transcription factors. In cancer cells however, activation of CD47 with TSP-1 increases proliferation of human U87 and U373 astrocytoma. it is likely that CD47 promotes proliferation via the PI3K/Akt pathway in cancerous cells but not normal cells (7).  Loss of CD47 allows sustained proliferation of primary murine endothelial cells and enables these cells to spontaneously reprogram to form multipotent embryoid body-like clusters (8).
  • Apoptosis – Ligation of CD47 by anti-CD47 mAbs was found to induce apoptosis in a number of different cell types (3). For example: Of the two SIRP-family members known to bind the CD47 IgV domain (SIRPα and SIRPγ), SIRPα as a soluble Fc-fusion protein does not induce CD47-dependent apoptosis, hile SIRPα or SIRPγ bound onto the surface of beads induces apoptosis through CD47 in Jurkat T cells and the myelomonocytic cell line U937.
  • Migration – CD47  role on cell migration was first demonstrated in neutrophils, these effects were shown to be dependent on avb3 integrins, which interact with and are activated by CD47 at the plasma membrane. In cancer, Blocking CD47 function has been shown to inhibit migration and metastasis in a variety of tumor models. Blockade of CD47 by neutralizing antibodies reduced migration and chemotaxis in response to collagen IV in melanomaprostate cancer and ovarian cancer-derived cells (9).
  • Angiogenesis – The mechanism of the anti-angiogenic activity of CD47 is not fully understood, but introduction of CD47 antibodies and TSP-1 have been shown to inhibit nitric oxide (NO)-stimulated responses in both endothelial and vascular smooth muscle cells (10). More so, CD47 signaling influences the SDF-1 chemokine pathway, which plays a role in angiogenesis (11). (12)
  • Inflammatory response – Interactions between endothelial cell CD47 and leukocyte SIRPγ regulate T cell transendothelial migration (TEM) at sites of inflammation. CD47 also functions as a marker of self on murine red blood cells which allows RBC to avoid phagocytosis. Tumor cells can also evade macrophage phagocytosis through the expression of CD47 (2, 13).

It appears that CD47 ligation induce different responses, depending on cell type and partner for ligation.

Therapeutic and clinical aspect of CD47 in human cancer:

CD47 is overexpressed in many types of human cancers  and its known function as a “don’t eat me” signal, suggests the potential for targeting the CD47-SIRPα pathway as a common therapy for human malignancies (2,13). Upregulation of CD47 expression in human cancers also appears to influence tumor growth and dissemination. First, increased expression of CD47 in several hematologic malignancies was found to be associated with a worse clinical prognosis, and in ALL to predict refractoriness to standard chemotherapies (13, 14-16). Second, CD47 was demonstrated to regulate tumor metastasis and dissemination in both MM and NHL (13, 17).

Efforts have been made to develop therapies inhibiting the CD47-SIRPα pathway, principally through blocking monoclonal antibodies directed against CD47, but also possibly with a recombinant SIRPα protein that can also bind and block CD47.

Figure 2

Chao MP et al. 2012 Combination strategies targeting CD47 in cancer

While monotherapies targeting CD47 were efficacious in several pre-clinical tumor models, combination strategies involving inhibition of the CD47-SIRPα pathway offer even greater therapeutic potential. Specifically, antibodies targeting CD47-SIRPα can be included in combination therapies with other therapeutic antibodies, macrophage-enhancing agents, chemo-radiation therapy, or as an adjuvant therapy to inhibit metastasis (13).

For example, anti-SIRPα antibody was found to potentiate  antibody-dependent cellular cytotoxicity (ADCC) mediated by the anti-Her2/Neu antibody trastuzumab against breast cancer cells (18).  CD47–SIRPα interactions and SIRPα signaling negatively regulate trastuzumab-mediated ADCC in vitro and antibody-dependent elimination of tumor cells in vivo

More so, chemo-radiation therapy-mediated upregulation of cell surface calreticulin may potentially augment the activity of anti-CD47 antibody. However, this approach may also lead to increased toxicity as cell surface calreticulin is expressed on non-cancerous cells undergoing apoptosis, a principle effect of chemo-radiation therapy (19).

Highlights:

  • Phagocytic cells, macrophages, regulate tumor growth through phagocytic clearance
  • CD47 binds SIRPα on phagocytes which delivers an inhibitory signal for phagocytosis
  • A blocking anti-CD47 antibody enabled phagocytic clearance of many human cancers
  • Phagocytosis depends on a balance of anti-(CD47) and pro-(calreticulin) signals
  • Anti-CD47 antibody synergized with an FcR-engaging antibody, such as rituximab

Summary

Evasion of immune recognition is a major mechanism by which cancers establish and propagate disease. Recent data has demonstrated that the innate immune system plays a key role in modulating tumor phagocytosis through the CD47-SIRPα pathway. Careful development of reagents that can block the CD47/SIRPα interaction may indeed be useful to treat many forms of cancer without having too much of a negative side effect in terms of inducing clearance of host cells. Therapeutic approaches inhibiting this pathway have demonstrated significant efficacy, leading to the reduction and elimination of multiple tumor types.

Dr. Weissman says: “We are now hopeful that the first human clinical trials of anti-CD47 antibody will take place at Stanford in mid-2014, if all goes wellClinical trials may also be done in the United Kingdom”. These clinical trials must be designed so that the data they generate will produce a valid scientific result!!!

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3. Oldenborg PL. CD47: A Cell Surface Glycoprotein Which Regulates Multiple Functions of Hematopoietic Cells in Health and Disease. ISRN Hematology Volume 2013 (2013), Article ID 614619, 19 pages.  http://www.hindawi.com/isrn/hematology/2013/614619/

4. G. Campbell, P. S. Freemont, W. Foulkes, and J. Trowsdale, “An ovarian tumor marker with homology to vaccinia virus contains an IgV- like region and multiple transmembrane domains,”Cancer Research, vol. 52, no. 19, pp. 5416–5420, 1992. http://cancerres.aacrjournals.org/content/52/19/5416.long

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6. CD47. Wikipedia. http://en.wikipedia.org/wiki/CD47

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8. Kaur S, Soto-Pantoja DR, Stein EV, Liu C, Elkahloun AG, Pendrak ML, Nicolae A, Singh SP, Nie Z, Levens D, Isenberg JS, Roberts DD.  “Thrombospondin-1 Signaling through CD47 Inhibits Self-renewal by Regulating c-Myc and Other Stem Cell Transcription Factors”Sci Rep 2013: 3: 1673. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3628113/

9. Shahan TA, Fawzi A, Bellon G, Monboisse JC, Kefalides NA. “Regulation of tumor cell chemotaxis by type IV collagen is mediated by a Ca(2+)-dependent mechanism requiring CD47 and the integrin alpha(V)beta(3)”. J. Biol. Chem 2000. 275 (7): 4796–4802. http://www.jbc.org/content/275/7/4796

10. Isenberg JS, Ridnour LA, Dimitry J, Frazier WA, Wink DA, Roberts DD. “CD47 is necessary for inhibition of nitric oxide-stimulated vascular cell responses by thrombospondin-1”. J. Biol. Chem  2006. 281 (36): 26069–26080.  http://www.jbc.org/content/281/36/26069

11. Smadja DM, d’Audigier C, Bièche I, Evrard S, Mauge L, Dias JV, Labreuche J, Laurendeau I, Marsac B, Dizier B, Wagner-Ballon O, Boisson-Vidal C, Morandi V, Duong-Van-Huyen JP, Bruneval P, Dignat-George F, Emmerich J, Gaussem P. “Thrombospondin-1 is a plasmatic marker of peripheral arterial disease that modulates endothelial progenitor cell angiogenic properties”. Arterioscler. Thromb. Vasc. Biol  2011. 31 (3): 551–559. http://atvb.ahajournals.org/content/31/3/551

12. G. D. Grossfeld, D. A. Ginsberg, J. P. Stein et al., “Thrombospondin-1 expression in bladder cancer: association with p53 alterations, tumor angiogenesis, and tumor progression,” Journal of the National Cancer Institute 1997 vol. 89, no. 3, pp. 219–227. http://www.scopus.com/record/display.url?eid=2-s2.0-18744423089&origin=inward&txGid=9C86356DDB0B6816ACCBF90F9CA44E92.WlW7NKKC52nnQNxjqAQrlA%3a2

13. Chao MP, Weissman IL, Majeti R. “The CD47-SIRPα pathway in cancer immune evasion and potential therapeutic implications”Curr. Opin. Immunol 2012. 24 (2): 225–32. http://www.sciencedirect.com/science/article/pii/S095279151200012Xhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC3319521/

14. Majeti R, Chao MP, Alizadeh AA, Pang WW, Jaiswal S, Gibbs KD, Jr, van Rooijen N, Weissman IL. Cd47 is an adverse prognostic factor and therapeutic antibody target on human acute myeloid leukemia stem cells. Cell. 2009;138(2):286–299. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2726837/

15. Chao MP, Alizadeh AA, Tang C, Jan M, Weissman-Tsukamoto R, Zhao F, Park CY, Weissman IL, Majeti R. Therapeutic antibody targeting of cd47 eliminates human acute lymphoblastic leukemia.Cancer Res. 2011;71 (4):1374–1384. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3041855/

16. Chao MP, Alizadeh AA, Tang C, Myklebust JH, Varghese B, Gill S, Jan M, Cha AC, Chan CK, Tan BT, Park CY, et al. Anti-cd47 antibody synergizes with rituximab to promote phagocytosis and eradicate non-hodgkin lymphoma. Cell. 2010;142(5):699–713. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2943345/

17. Chao MP, Tang C, Pachynski RK, Chin R, Majeti R, Weissman IL. Extranodal dissemination of non-hodgkin lymphoma requires cd47 and is inhibited by anti-cd47 antibody therapy. Blood.2011;118(18):4890–4901. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3208297/

18. Zhao XW, van Beek EM, Schornagel K, Van der Maaden H, Van Houdt M, Otten MA, Finetti P, Van Egmond M, Matozaki T, Kraal G, Birnbaum D, et al. Cd47-signal regulatory protein-alpha (sirpalpha) interactions form a barrier for antibody-mediated tumor cell destruction. Proc Natl Acad Sci U S A.2011;108(45):18342–18347. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3215076/

19. Obeid M, Tesniere A, Ghiringhelli F, Fimia GM, Apetoh L, Perfettini JL, Castedo M, Mignot G, Panaretakis T, Casares N, Metivier D, et al. Calreticulin exposure dictates the immunogenicity of cancer cell death. Nat Med. 2007;13(1):54–61. http://www.ncbi.nlm.nih.gov/pubmed/17187072

Other related articles on this Open Access Online Scientific Journal include the following:

I. By: Larry Bernstein MD. Treatment for Metastatic HER2 Breast Cancer https://pharmaceuticalintelligence.com/2013/03/03/treatment-for-metastatic-her2-breast-cancer/

II. By: Tilda Barliya PhD. Colon Cancer.  https://pharmaceuticalintelligence.com/2013/04/30/colon-cancer/

III. By: Ritu Saxena PhD. In focus: Triple Negative Breast Cancer. https://pharmaceuticalintelligence.com/2013/01/29/in-focus-triple-negative-breast-cancer/

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