Antibody drug conjugates (ADCs)
Larry H. Bernstein, MD, FCAP: Curator
LPBI
UPDATED 6/01/2024
Below are a curation of reports highlighting both clinical trial failures and serious adverse events reported from clinical trials of various antibody drug or antibody radioligand conjugates. As see below, there have been mutliple failures of these types of biological entitites in oncology clinical trials, either displaying issues related to efficacy and/or safety.
Source: https://www.fiercebiotech.com/biotech/asco-jjs-radioligand-spurs-responses-4-deaths-mar-early-results
ASCO: J&J’s radioligand spurs responses, but 4 deaths mar early results
By Annalee Armstrong May 24, 2024
Johnson & Johnson’s radiopharmaceutical spurred “profound and durable” responses, however, four patient deaths in the early-stage trial marred the results.
JNJ-6420 is an anti-hK2 antibody-based targeted radioligand therapy that’s designed to deliver a high-energy, short-range alpha-particle emitter to prostate cancer cells. The first-in-human study tested the radiopharmaceutical in patients with metastatic castration-resistant prostate cancer who have previously received at least one prior androgen receptor pathway inhibitor. The results are to be presented next week at the American Society of Clinical Oncology conference. The goal of the phase 1 dose-escalation study was to demonstrate the drug’s safety and to find a dose to move into phase 2. In one trial group, 37 patients were on a fixed dosing starting schedule, receiving between 50 μCi and up to 300 μCi. Twenty-nine patients in the other trial group were capped at a cumulative 500-μCi dose. As of the Jan. 5 data cutoff, 64 patients had received at least one dose of JNJ-6420, with safety data being recorded for 57 patients who had received 150 μCi. Of these patients, 35, or 61%, experienced grade 3 or higher treatment-emergent adverse events (TEAEs), and 21, or 37%, had a serious TEAE. Almost all patients experienced some sort of TEAE. There were four deaths due to TEAEs, which were associated with repeated dosing of JNJ-6420. The full data set linked two of the deaths to interstitial lung disease (ILD), one to respiratory failure related to COVID-19 and one to decreased appetite/hypotension. ILD is a common adverse event in oncology treatment, particularly for antibody-drug conjugates. The condition causes progressive scarring of lung tissue. The deaths related to ILD occurred in patients who had received cumulative doses greater than or equal to 750 μCi. To address the risk of ILD and thrombocytopenia, the study investigators are recommending a cumulative dose cap and an adaptive dose schedule. Evaluation of adaptive dosing is ongoing. Other common TEAEs in the study included anemia and two conditions related to low white blood cells, lymphopenia and leukopenia. Nine patients discontinued treatment. As for the responses, the data showed a reported PSA50 rate of 45.6%. This is a measure of prostatic-specific antigen, which is a key biomarker in prostate cancer. A PSA response is associated with prolonged overall survival.
ADC puts Zynlonta study on hold after 7 patient deaths, 5 other severe adverse events (2023)
Source: https://www.fiercepharma.com/pharma/adc-therapeutics-puts-zynlonta-study-enrollment-pause-after-seven-patient-deaths-five-other
By Zoey Becker Jul 11, 2023
DC Therapeutics has slammed the brakes on enrollment in a phase 2 combination trial for Zynlonta as it investigates seven patient deaths and five other severe respiratory events among patients who received the drug.
For the study in unfit or frail patients with previously untreated diffuse large B-cell lymphoma (DLBCL), investigators had enrolled 40 participants. After receiving the ADC drug, 12 of them experienced respiratory-related, treatment-emergent adverse events, ADC said in a Tuesday release.
The investigators concluded that 11 of the events, including six of the deaths, were “unrelated” to the Zynlonta treatment or unlikely to be related to the drug, ADC said. All of the patients who died suffered from at least one “significant” comorbidity, including obstructive pulmonary disease, pulmonary edema, chronic bronchiectasis, idiopathic pulmonary fibrosis or recent COVID-19 infection. All of the patients who passed away were at least 80 years of age, according to the company. ADC said it put a “voluntary pause” on the trial to gain more time to “evaluate data … and determine next steps.” The study was testing ADC’s medicine in combination with Roche’s Rituxan. “Our top priority is the safety of every patient who participates in our clinical trials,” CEO Ameet Mallik said in the company’s statement. “This trial includes a very difficult-to-treat patient population with limited treatment options, and we will provide an update on next steps when available.” ADC has notified the FDA and the European Medicines Agency (EMA) and doesn’t expect to report any additional trial data by the end of the year.
However in 2024 from ADC Therapeutics site
ZYNLONTA® 1 4Q 2023 net sales expected to be ~$16.5 million, a double-digit percentage increase as compared to 3Q 2023
LOTIS-7: Study of ZYNLONTA in combination with bispecifics cleared first dosing cohort with no DLT and with early signs of efficacy
ADCT-601 (targeting AXL): Reached MTD and currently in dose optimization; Early signs of antitumor activity in both monotherapy and in combination
Multiple data catalysts expected in 2024 and with a cash runway now expected into 4Q 2025
LAUSANNE, Switzerland, Jan. 04, 2024 (GLOBE NEWSWIRE) — ADC Therapeutics SA (NYSE: ADCT) today provided business updates.
“During 2023, we took a number of decisive actions to help position the Company for success in 2024 and beyond. We prioritized our pipeline, strengthened our organization and implemented a disciplined capital allocation model to generate cost efficiencies,” said Ameet Mallik, Chief Executive Officer of ADC Therapeutics. “We believe we are starting to see signs of the commercial turnaround. We are also encouraged to see positive initial signals in the LOTIS-7 trial of ZYNLONTA in combination with bispecifics as well as early signs of antitumor activity in the Phase 1b trial of ADCT-601. We now expect our cash runway to extend into the fourth quarter of 2025 and believe we are on a path to unlock the substantial value in the Company.”
Source: ADC Therapeutics Press Release at https://ir.adctherapeutics.com/press-releases/press-release-details/2024/ADC-Therapeutics-Provides-Business-Updates/default.aspx
Processes for Constructing Homogeneous Antibody Drug Conjugates
by DR ANTHONY MELVIN CRASTO Ph.D
Processes for Constructing Homogeneous Antibody Drug Conjugates
† Igenica Biotherapeutics, 863A Mitten Road, Suite 100B, Burlingame, California 94010, United States
Org. Process Res. Dev., Article ASAP
Antibody drug conjugates (ADCs) are synthesized by conjugating a cytotoxic drug or “payload” to a monoclonal antibody. The payloads are conjugated using amino or sulfhydryl specific linkers that react with lysines or cysteines on the antibody surface. A typical antibody contains over 60 lysines and up to 12 cysteines as potential conjugation sites. The desired DAR (drugs/antibody ratio) depends on a number of different factors and ranges from two to eight drugs/antibody. The discrepancy between the number of potential conjugation sites and the desired DAR, combined with use of conventional conjugation methods that are not site-specific, results in heterogeneous ADCs that vary in both DAR and conjugation sites. Heterogeneous ADCs contain significant fractions with suboptimal DARs that are known to possess undesired pharmacological properties. As a result, new methods for synthesizing homogeneous ADCs have been developed in order to increase their potential as therapeutic agents. This article will review recently reported processes for preparing ADCs with improved homogeneity. The advantages and potential limitations of each process are discussed, with emphasis on efficiency, quality, and in vivo efficacy relative to similar heterogeneous ADCs.
Antibody drug conjugates (ADCs) are a rapidly growing class of targeted therapeutic agents for treatment of cancer.(1-8) Although the number of ADCs in clinical trials has steadily increased since 2005, many have failed to reach the later stages of clinical development; one has been withdrawn from the market (Mylotarg in 2002), and only two (Adcetris and Kadcyla) are currently approved by the FDA for cancer indications (Figure 1A).(9-11) Thus, far, the approval rate for ADCs has not met early expectations and is lagging behind other antibody-based therapeutics. Based on the number of approved ADCs versus those that have failed to progress into later stage clinical trials, the success rate is reminiscent of that for small molecule drugs. The reasons for the clinical failures of ADCs are often not known or they are still under investigation. More commonly, when the reasons for clinical failure are clear, the information is not made available to the public domain. Emerging preclinical data suggests that heterogeneity, a property shared by most ADCs currently in clinical development (Table 1), may ultimately limit their potential as therapeutic agents.(12, 13)
Table 1. Examples of Heterogeneous ADCs Currently in Clinical Trials for Cancer Indicationsa
a Source: www.clinicaltrials.gov.
http://pubs.acs.org/appl/literatum/publisher/achs/journals/content/oprdfk/0/oprdfk.ahead-of-print/acs.oprd.6b00067/20160428/images/large/op-2016-00067k_0001.jpeg
Figure 1. (A) Number of ADCs in different stages of clinical development from 2006 to 2014. (B) Structure of a typical IgG antibody showing lysines (red), cysteines (yellow), and glycans (green) as potential conjugation sites.(16)
ADCs are composed of a cytotoxic drug or “payload” conjugated to a tumor selective monoclonal antibody. The heterogeneity of conventional ADCs arises from the synthetic processes currently used for conjugation.
(14) Payloads are typically conjugated to the antibody using amino or thiol specific linkers that react with lysines or cysteines on the antibody surface.
(15) A typical antibody contains more than 50 lysines and up to 12 cysteines as potential conjugation sites (
Figure 1B).
(16) The optimal DAR (drugs/antibody ratio) for most ADCs, however, ranges from 2 to 8 drugs/antibody and is dependent upon a variety of different factors. The discrepancy between the number of potential conjugation sites and the desired DAR, combined with the use of conjugation methods that are not site-specific, result in heterogeneous ADCs that vary in both DAR and conjugation sites. Consequently, conventional heterogeneous ADCs often contain significant amounts of unconjugated antibody in addition to fractions with suboptimal DARs. Unconjugated antibodies can compete for antigen binding and inhibit ADC activity, while fractions with suboptimal DARs are frequently prone to aggregation, poor solubility, and/or instability that ultimately result in a poor therapeutic window.
(17, 18)The relative degree of ADC heterogeneity depends on the methods used for conjugation. For example, Kadcyla, an ADC approved in 2013 for breast cancer, is synthesized using a two-step process in which the linker and payload are conjugated in separate steps (
Scheme 1A).
(19-21)The linker contains an amino-specific NHS ester that reacts with antibody lysines in the first step and a thiol-specific maleimide group that reacts with a maytansinoid payload in the second step. The process affords a highly heterogeneous mixture of ADC molecules containing from 0 to 10 payloads/antibody with an average DAR of 3.5 drugs/antibody.
(22, 23) Additional heterogeneity arises due to distribution of the payloads across dozens of potential conjugation sites. As a result, Kadcyla contains hundreds of different ADC molecules, each with its own unique pharmacological properties.
(24)
Scheme 1. (A) General Process for Synthesizing ADCs such as Kadcyla via Lysine Conjugation; (B) General Process for Synthesizing ADCs, such as Adcetris, via Cysteine Conjugation
Conjugation of payloads to antibodies through interchain cysteines reduces ADC heterogeneity relative to lysine conjugation because there are fewer potential conjugation sites. Adcetris, an ADC approved in 2011 for treatment of Hodgkin’s lymphoma, is an example of a cysteine conjugated ADC.
(25-27) The process for cysteine conjugation involves partial reduction of four antibody interchain disulfide bonds to generate up to eight reactive thiol groups. The partially reduced antibody is subsequently conjugated to a payload containing a thiol-specific maleimide linker. The payload used for Adcetris is monomethyl auristatin E (MMAE) and contains a protease cleavable maleimide linker (
Scheme 1B). Although Adcetris is less heterogeneous than Kadcyla, it is composed of dozens of different ADC molecules containing 0 to 8 payloads with an average DAR of 3.6 drugs/antibody.
(28) Like most cysteine conjugated ADCs, Adcetris has a reduced half-life in vivo compared to the parent antibody, cAC10. The diminished half-life has been attributed to rapid clearance of high DAR species (>4 drugs/antibody) and to partial loss of interchain disulfide bonds during the conjugation process.
(29, 30)Although different processes for lysine and cysteine conjugation are used to synthesize Adcetris and Kadcyla, both ADCs contain thio-succinimide bonds between the payload and the antibody, which originate from the use of maleimide linkers in the conjugation processes. Kadcyla contains a thio-succinimide between the linker and the payload (
Scheme 1A), while Adcetris contains a thio-succinimide bond between the linker and the antibody (
Scheme 1B). Thio-succinimide groups are known to undergo undesired side reactions such as elimination or thiol exchange that can result in premature release of the payloads from the ADC and lead to reduced potency and/or increased systemic toxicity.
(31, 32)Despite the known limitations of conventional heterogeneous ADCs, most ADCs currently in clinical development utilize similar conjugation methods to those described in
Scheme 1. As a result, they are likely to possess similar pharmacological properties to Adcetris and Kadcyla, in addition to other less successful ADCs that may have performed poorly in clinical trials. In order to improve the pharmacological properties of current and future ADCs, new site-specific conjugation processes for synthesizing homogeneous ADCs are now being developed.
(33-36)Site-specific conjugation processes for constructing homogeneous ADCs can be divided into three different categories. Two are focused on antibody modification (engineered amino acids and enzyme mediated), while the third category is focused on linker modification. The categories can be subdivided further based on the specific processes that are used (
Table 2). Examples from each process were selected based on availability of sufficient preclinical data to enable comparison with similar conventional heterogeneous ADCs. Homogeneous ADCs derived from these processes have only just begun to enter clinical trials. Whether they will outperform their heterogeneous counterparts in clinical trials remains uncertain, but preclinical data suggest that homogeneous ADCs are likely to dominate future clinical trials and will lead to improved clinical results.
…….
All of the processes reviewed here were successfully used to construct ADCs with improved homogeneity over ADCs synthesized using conventional methods. A majority of approaches utilize recombinant antibody engineering to introduce unique functional groups for site-specific conjugation. The unique functional groups were introduced either as point mutations for cysteine and non-natural amino acids or as enzyme recognition tags. These recombinant engineering approaches offer several potential advantages over nonrecombinant approaches. For example, engineered cysteines can be incorporated into dozens of different sites with minimal impact on the functional properties of the antibody. This enables ADCs to be optimized for conjugation efficiency, linker stability, and potency. Engineered non-natural amino acids offer additional advantages due to the diverse array of different functional groups that can be introduced. Furthermore, non-natural amino acids enable a variety of new linker chemistries to be investigated that are not possible with conventional conjugation processes.
The flexibility offered by recombinant processes may also represent their greatest challenge. The importance of the conjugation site for ADC activity is well-established, but additional factors should be considered before selecting a development candidate. Potential effects on antibody expression, conjugation efficiency, linker stability, aggregation, and other factors need to be considered before selecting a specific conjugation site. These factors can ultimately determine the success or failure of an ADC development program. Since antibodies share many of the same properties, it seems likely that optimal conjugation sites will be identified that are broadly effective when used with different antibodies. Other potential challenges for processes involving antibody engineering include increased development time and costs, immunogenicity of engineered sequence tags, scalability, and use of novel linkers and payloads that are not yet clinically validated.
In addition to homogeneity, improvements in other ADC properties such as potency, stability and half-life were observed. In fact, many of the homogeneous ADCs derived from these processes out-performed conventional heterogeneous ADCs in efficacy and safety studies. Much of their success has been attributed to elimination of high DAR species present in conventional ADCs. In general, experimental results are consistent with this conclusion, and many would agree that substantial progress has resulted from these efforts to improve ADC homogeneity. Ironically, the relative contribution of homogeneity to the improved properties of the engineered ADCs could not be determined from most studies because other factors known to effect ADC activity could not be ruled out.
For instance, recombinant approaches for making homogeneous ADCs were designed to introduce conjugation sites in different locations from those used in conventional methods. Since it is now well-established that “location matters”, the observed differences in activity between TDCs (or NDCs) and the conventional ADC controls could result from different conjugation sites, rather than from elimination of high DAR species. Enzyme mediated approaches face similar challenges when comparing homogeneous and heterogeneous ADCs because the conjugation sites are different. Other variables such as linker type (cleavable or noncleavable) and payload (maytansine or PBD) need to be carefully controlled before reaching conclusions about the benefits of homogeneity.
Linker based processes are more suitable for comparing homogeneous ADCs with conventional heterogeneous ADCs because they utilize the same conjugation sites. Once other variables that might impact ADC activity were carefully controlled, the relative benefits of homogeneity were revealed for the first time and the results confirmed that efforts to improve ADC homogeneity have been a worthwhile endeavor.
Most of the processes reviewed here are still in early phases of clinical development. All of the methods have advantages and limitations that will ultimately decide which approach will become the preferred process for manufacturing homogeneous ADCs. It is not yet clear which process will rise above the others as a preferred method, but all of these approaches have contributed valuable information to our knowledge base and resulted in ADCs with improved pharmacological properties over conventional heterogeneous ADCs. Our future challenge will be to apply this knowledge to develop ADCs that will be more effective as therapeutic agents. Our ability to synthesize homogeneous ADCs provides another reason to be optimistic about the future of ADCs.
ACS Editors’ Choice – This is an open access article published under an ACS AuthorChoice
License, which permits copying and redistribution of the article or any adaptations for non-commercial purposes.
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