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Posts Tagged ‘antibody-drug conjugate’


Inhibitory CD161 receptor recognized as a potential immunotherapy target in glioma-infiltrating T cells by single-cell analysis

Reporter: Dr. Premalata Pati, Ph.D., Postdoc

 

Brain tumors, especially the diffused Gliomas are of the most devastating forms of cancer and have so-far been resistant to immunotherapy. It is comprehended that T cells can penetrate the glioma cells, but it still remains unknown why infiltrating cells miscarry to mount a resistant reaction or stop the tumor development.

Gliomas are brain tumors that begin from neuroglial begetter cells. The conventional therapeutic methods including, surgery, chemotherapy, and radiotherapy, have accomplished restricted changes inside glioma patients. Immunotherapy, a compliance in cancer treatment, has introduced a promising strategy with the capacity to penetrate the blood-brain barrier. This has been recognized since the spearheading revelation of lymphatics within the central nervous system. Glioma is not generally carcinogenic. As observed in a number of cases, the tumor cells viably reproduce and assault the adjoining tissues, by and large, gliomas are malignant in nature and tend to metastasize. There are four grades in glioma, and each grade has distinctive cell features and different treatment strategies. Glioblastoma is a grade IV glioma, which is the crucial aggravated form. This infers that all glioblastomas are gliomas, however, not all gliomas are glioblastomas.

Decades of investigations on infiltrating gliomas still take off vital questions with respect to the etiology, cellular lineage, and function of various cell types inside glial malignancies. In spite of the available treatment options such as surgical resection, radiotherapy, and chemotherapy, the average survival rate for high-grade glioma patients remains 1–3 years (1).

A recent in vitro study performed by the researchers of Dana-Farber Cancer Institute, Massachusetts General Hospital, and the Broad Institute of MIT and Harvard, USA, has recognized that CD161 is identified as a potential new target for immunotherapy of malignant brain tumors. The scientific team depicted their work in the Cell Journal, in a paper entitled, “Inhibitory CD161 receptor recognized in glioma-infiltrating T cells by single-cell analysis.” on 15th February 2021.

To further expand their research and findings, Dr. Kai Wucherpfennig, MD, PhD, Chief of the Center for Cancer Immunotherapy, at Dana-Farber stated that their research is additionally important in a number of other major human cancer types such as 

  • melanoma,
  • lung,
  • colon, and
  • liver cancer.

Dr. Wucherpfennig has praised the other authors of the report Mario Suva, MD, PhD, of Massachusetts Common Clinic; Aviv Regev, PhD, of the Klarman Cell Observatory at Broad Institute of MIT and Harvard, and David Reardon, MD, clinical executive of the Center for Neuro-Oncology at Dana-Farber.

Hence, this new study elaborates the effectiveness of the potential effectors of anti-tumor immunity in subsets of T cells that co-express cytotoxic programs and several natural killer (NK) cell genes.

The Study-

IMAGE SOURCE: Experimental Strategy (Mathewson et al., 2021)

 

The group utilized single-cell RNA sequencing (RNA-seq) to mull over gene expression and the clonal picture of tumor-infiltrating T cells. It involved the participation of 31 patients suffering from diffused gliomas and glioblastoma. Their work illustrated that the ligand molecule CLEC2D activates CD161, which is an immune cell surface receptor that restrains the development of cancer combating activity of immune T cells and tumor cells in the brain. The study reveals that the activation of CD161 weakens the T cell response against tumor cells.

Based on the study, the facts suggest that the analysis of clonally expanded tumor-infiltrating T cells further identifies the NK gene KLRB1 that codes for CD161 as a candidate inhibitory receptor. This was followed by the use of 

  • CRISPR/Cas9 gene-editing technology to inactivate the KLRB1 gene in T cells and showed that CD161 inhibits the tumor cell-killing function of T cells. Accordingly,
  • genetic inactivation of KLRB1 or
  • antibody-mediated CD161 blockade

enhances T cell-mediated killing of glioma cells in vitro and their anti-tumor function in vivo. KLRB1 and its associated transcriptional program are also expressed by substantial T cell populations in other forms of human cancers. The work provides an atlas of T cells in gliomas and highlights CD161 and other NK cell receptors as immune checkpoint targets.

Further, it has been identified that many cancer patients are being treated with immunotherapy drugs that disable their “immune checkpoints” and their molecular brakes are exploited by the cancer cells to suppress the body’s defensive response induced by T cells against tumors. Disabling these checkpoints lead the immune system to attack the cancer cells. One of the most frequently targeted checkpoints is PD-1. However, recent trials of drugs that target PD-1 in glioblastomas have failed to benefit the patients.

In the current study, the researchers found that fewer T cells from gliomas contained PD-1 than CD161. As a result, they said, “CD161 may represent an attractive target, as it is a cell surface molecule expressed by both CD8 and CD4 T cell subsets [the two types of T cells engaged in response against tumor cells] and a larger fraction of T cells express CD161 than the PD-1 protein.”

However, potential side effects of antibody-mediated blockade of the CLEC2D-CD161 pathway remain unknown and will need to be examined in a non-human primate model. The group hopes to use this finding in their future work by

utilizing their outline by expression of KLRB1 gene in tumor-infiltrating T cells in diffuse gliomas to make a remarkable contribution in therapeutics related to immunosuppression in brain tumors along with four other common human cancers ( Viz. melanoma, non-small cell lung cancer (NSCLC), hepatocellular carcinoma, and colorectal cancer) and how this may be manipulated for prevalent survival of the patients.

References

(1) Anders I. Persson, QiWen Fan, Joanna J. Phillips, William A. Weiss, 39 – Glioma, Editor(s): Sid Gilman, Neurobiology of Disease, Academic Press, 2007, Pages 433-444, ISBN 9780120885923, https://doi.org/10.1016/B978-012088592-3/50041-4.

Main Source

Mathewson ND, Ashenberg O, Tirosh I, Gritsch S, Perez EM, Marx S, et al. 2021. Inhibitory CD161 receptor identified in glioma-infiltrating T cells by single-cell analysis. Cell.https://www.cell.com/cell/fulltext/S0092-8674(21)00065-9?elqTrackId=c3dd8ff1d51f4aea87edd0153b4f2dc7

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Spirogen’s Cytotoxic Warheads IP Taken over for $400 Million by AstraZeneca PLC (AZN)’s MedImmune (AZN) for Avoidance Capabilities of Emergent Drug Resistance

Reporter: Aviva Lev-Ari, PhD, RN

AstraZeneca PLC (AZN)’s MedImmune (AZN) Takes OverSpirogen Ltd. for Up to $400 Million to Bolster Oncolology Portfolio

10/15/2013 7:54:15 AM

 

AstraZeneca PLC Oncology Portfolio Strengthened as MedImmune Acquisition of Spirogen Ltd. Boosts Antibody-Drug Conjugate Capability 

AstraZeneca PLC Oncology Portfolio Strengthened as MedImmune Acquisition of Spirogen Ltd. Boosts Antibody-Drug Conjugate Capability 

Tuesday, 15 October 2013 — AstraZeneca today announced that MedImmune, its global biologics research and development arm, has acquired Spirogen, a privately-held biotech company focused on antibody-drug conjugate technology for use in oncology.

MedImmune has also entered into a collaboration agreement with ADC Therapeutics to jointly develop two of ADC Therapeutics’ antibody-drug conjugate programmes in preclinical development. MedImmune will also make an equity investment in ADC Therapeutics, which has an existing licensing agreement with Spirogen.

MedImmune will acquire 100 per cent of Spirogen’s shares for an initial consideration of $200 million and deferred consideration of up to $240 million based on reaching predetermined development milestones. Existing out-licensing agreements and associated revenue streams are excluded from this acquisition.

MedImmune will also pay $20 million for an equity investment in ADC Therapeutics, which will be matched by Auven Therapeutics, the majority shareholder in both ADC Therapeutics and Spirogen. The collaboration agreement will include an upfront payment with predetermined development milestones for two programmes from a defined list and a cost- and profit-sharing arrangement with MedImmune representing the majority share. ADC Therapeutics will also have the option to co-promote one of the products in the US.

Antibody-drug conjugates are a clinically-validated cancer drug technology that offers both high potency and selective targeting of cancer cells. Spirogen’s proprietary pyrrolobenzodiazepine (PBD) technology attaches highly potent cytotoxic agents, or ‘warheads’ to specific cancer-targeting antibodies using biodegradable ‘linkers’. This targeting optimises the delivery of the cancer drug to the tumour cells only and provides the greatest degree of tumour killing while minimising the toxicity to the patient.

“Antibody-drug conjugates are ground-breaking technologies with the potential for directly targeting many types of cancer tumours while safeguarding healthy cells. The cutting-edge technologies developed by Spirogen and ADC Therapeutics complement MedImmune’s innovative antibody engineering capabilities, enabling us to accelerate antibody-drug conjugates into the clinic,” said Dr. Bahija Jallal, Executive Vice President, MedImmune.

Oncology is a core therapy area for AstraZeneca spanning both small molecule and biologics research and development. MedImmune is developing a comprehensive portfolio with an emphasis on two key areas in oncology development: antibody-drug conjugates and immune-mediated cancer therapy, which aims to harness the power of the patient’s own immune system to fight cancer. Together, immune-mediated cancer therapies and antibody-drug conjugates have the potential to treat cancer in a way that current therapies are unable to do.

“This deal reflects the very significant progress made by our scientists, most notably over the last two years, as we have applied our warhead and linker technologies to the development of highly potent and specific antibody-drug conjugates,” said Dr. Chris Martin, Chief Executive Officer, Spirogen. “We believe that pyrrolobenzodiazepine-armed antibody-drug conjugates will emerge as a critical component in the next generation of cancer biologics with the potential to make a difference for oncologists and their patients. We look forward to combining our world-class capabilities in this area with MedImmune’s ability to develop this exciting class of oncology drugs.”

About Antibody-Drug Conjugates

An antibody-drug conjugate is a three-component system consisting of a potent cytotoxic agent, or ‘warhead’, a biodegradable linker and a monoclonal antibody. The antibody binds to specific markers at the surface of the cancer cell. The whole antibody-drug conjugate is then internalised within the cancer cell where the active drug is released. Antibody-drug conjugates have extensive potential therapeutic applications in several disease areas, particularly in cancer. The principle can also be applied beyond antibodies, with the possibility of linking warheads to antibody fragments, peptides, vitamins and hormones.

About Spirogen

The Spirogen group was founded in 2001 as a spin-out from several institutions including University College London and with partial funding by Cancer Research UK. It is majority owned by Auven Therapeutics. It has developed a novel class of highly potent cytotoxic warheads based on its proprietary pyrrolobenzodiazepines (PBDs), DNA minor groove binding agents, which bind and cross-link specific sites of DNA of the cancer cell. This blocks the cancer cells’ division without distorting its DNA helix, thus potentially avoiding the common phenomenon of emergent drug resistance. Spirogen has been developing its PBD technology for more than ten years, including a standalone PBD agent in a Phase II study in acute myeloid leukemia. Its business model has been to partner its technology with pharma and biotech for use in the development of novel drugs. It has a number of industry collaborations, including collaborations with Genentech announced in 2011 and with ADC Therapeutics announced in 2012. For further information, please visit: http://www.spirogen.com.

About ADC Therapeutics

ADC Therapeutics (ADCT) is a Swiss-based oncology drug development company that specialises in the development of proprietary antibody-drug conjugates (ADCs) targeting major cancers such as breast, lung, prostate, renal and blood. The company’s ADCs are highly targeted drug constructs which combine monoclonal antibodies specific to particular types of tumour cells with a novel class of highly potent PBD-based warheads. The company was launched in 2012 with a $50m commitment from private equity firm Auven Therapeutics. ADCT has access to warhead and linker chemistries via existing agreements with Spirogen. It operates a virtual business model based in Lausanne, Switzerland. For further information, please visit: http://www.adctherapeutics.com.

About Auven Therapeutics

Auven Therapeutics was founded by Stephen Evans-Freke and Dr. Peter B Corr in 2007 with an innovative investment strategy that enables it to operate as a drug development company while remaining structured as a private equity fund. Auven Therapeutics has a portfolio of biologic and small molecule drug candidates for a range of therapeutic indications including cancer, ophthalmic conditions, women’s health and orphan diseases. Auven manages its drug development activities from its bases in Lausanne, Switzerland, New York, USA and Hamilton, Bermuda. Auven Therapeutics Management LLLP, based in the US Virgin Islands, serves as its Investment Advisor. For further information, please visit: http://www.auventx.com.

About MedImmune

MedImmune is the worldwide biologics research and development arm of AstraZeneca. MedImmune is pioneering innovative research and exploring novel pathways across key therapeutic areas, including respiratory, inflammation and autoimmunity; cardiovascular and metabolic disease; oncology; neuroscience, and infection and vaccines. The MedImmune headquarters is located in Gaithersburg, MD, one of AstraZeneca’s three global R&D centres. For more information, please visit http://www.medimmune.com.

About AstraZeneca

AstraZeneca is a global, innovation-driven biopharmaceutical business that focuses on the discovery, development and commercialisation of prescription medicines, primarily for the treatment of cardiovascular, metabolic, respiratory, inflammation, autoimmune, oncology, infection and neuroscience diseases. AstraZeneca operates in over 100 countries and its innovative medicines are used by millions of patients worldwide. For more information please visit: http://www.astrazeneca.com

SOURCE

http://www.biospace.com/news_story.aspx?NewsEntityId=311765&type=email&source=DD_101513

 

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Treatment for Metastatic HER2 Breast Cancer

Screen Shot 2021-07-19 at 7.34.43 PM

Word Cloud By Danielle Smolyar

Reporter: Larry H Bernstein, MD, FCAP
Leaders in Pharmaceutical Innovation
https://pharmaceuticalintelligence.com/2013/03/03/9680/Treatment for Metastatic HER2 Breast Cancer 

FDA Approves New Treatment for Metastatic HER2 Breast Cancer (antibody-drug conjugate)
T-DM1 is indicated for patients who were previously treated with the anti-HER2 therapy trastuzumab (Herceptin, Genentech) and a taxane chemotherapy.

The US Food and Drug Administration (FDA) today approved ado-trastuzumab emtansine (Kadcyla, Genentech), also known as T-DM1, for the treatment of patients with HER2-positive metastatic breast cancer.
T-DM1 is indicated for patients who were previously treated with

  • the anti-HER2 therapy trastuzumab (Herceptin, Genentech) and a taxane chemotherapy.

This product offers a new twist on an older product; it is an antibody–drug conjugate in which the

  • HER2-targeted antibody trastuzumab
  • is chemically linked to the cytotoxin mertansine (DM1).

The antibody homes in on HER2 breast cancer cells, delivering the chemotherapy directly to the tumor, which reduces the risk for toxicity.  According to Richard Pazdur, MD, at the FDA Center for Drug Evaluation and Research, T-DM1 carries the drug-conjugate

  • directly to the cancer site
  • to shrink the tumor,
  • slow disease progression, and
  • prolong survival .

It is the fourth drug approved that targets the HER2 protein. Apart from lapatinib, which is marketed by GlaxoSmithKline, all the other HER2-targeted products have been developed and are marketed by Genentech/Roche. For T-DM1, the proprietary technology involved in the DM1 portion of the product was developed by ImmunoGen, working in collaboration with Genentech/Roche.

In the pivotal phase 3 EMILIA study, patients receiving T-DM1 survived nearly 6 months longer than patients receiving the standard therapy of

  • lapatinib (Tykerb) plus capecitabine (Xeloda) (median overall survival, 30.9 vs 25.1 months).

There were fewer grade 3 or higher (severe) adverse events with TDM-1 than with standard therapy

  • 43.1% vs. 59.2%)

The approval represents a “momentous” day in breast cancer, said Kathy Miller, MD, from Indiana University in Indianapolis, in her Miller on Oncology Medscape blog.

  • HER2-positive patients with metastatic disease have a therapy that offers prolonged disease control with less toxicity

 T-DM1 was more effective in EMILIA than standard therapy on every outcome:

  • overall response rate,
  • disease-free survival,
  • progression-free survival, and
  • overall survival.

Herceptin Fab (antibody) - light and heavy chains

Herceptin Fab (antibody) – light and heavy chains (Photo credit: Wikipedia)

Ribbon diagram of the Fab fragment of , a , bo...

Ribbon diagram of the Fab fragment of , a , bound to the extracellular domain of HER2. Created using Accelrys DS Visualizer Pro 1.6 and . ; Legend Trastuzumab Fab fragment, Trastuzumab Fab fragment, HER2, extracellular domain (Photo credit: Wikipedia)

Breast cancer (Infiltrating ductal carcinoma o...

Breast cancer (Infiltrating ductal carcinoma of the breast) assayed with anti HER-2 (ErbB2) antibody. (Photo credit: Wikipedia)

English: Breast cancer incidence by age in wom...

English: Breast cancer incidence by age in women in the United Kingdom 2006-2008. Reference: Excel chart for Figure 1.1: Breast Cancer (C50), Average Number of New Cases per Year and Age-Specific Incidence Rates, UK, 2006-2008 at Breast cancer – UK incidence statistics at Cancer Research UK. Section updated 18/07/11. (Photo credit: Wikipedia)

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