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You are here: Home / Archives for Antibody drug conjugates

Discovering and Targeting Neo-epitopes in Cancer

March 17, 2022 by The Antibody Society

Antibody Engineering & Therapeutics, held in December 2021, offered many opportunities to hear exciting and informative presentations by experts in the field. We are pleased to present here a summary of a plenary lecture by Prof. James Wells (USCF), kindly written by Dr. Czeslaw Radziejewski.

 


Discovering and Targeting Neo-epitopes in Cancer.
James Wells
, Professor and Chair, Department of Pharmaceutical Chemistry, UCSF

Professor Wells presented the plenary lecture on the identification of cancer-associated proteolytic neo-epitopes in cell membrane proteins and the identification of novel cancer-specific MHC-1 peptide complexes. Cell surface proteins are the targets of most biologic and small molecule drugs. Professor Wells and colleagues use cell surface proteomics to examine changes in the cell surface proteins upon transformation with oncogenes such as KRAS, HER2, EGFR, BRAF, MEK, and Myc. Ecto-domains of identified proteins, which generally belong to the single pass trans-membrane class, are expressed as Fc fusion proteins and antibodies are generated against these proteins via screening phage libraries. Specificities of the antibodies are verified by testing against full-length trans-membrane proteins expressed by cells transfected with appropriate vectors.

Proteolysis is a primary post-translational modification of cell surface proteins. There are approximately 500 human proteases, and proteolysis plays an important role in disease progression, such as angiogenesis, invasion and metastasis, inflammation, and immune evasion. Well’s lab is exploring methods to identify proteolytic cleavage sites on the surfaceome of cancer cells.[1] To accomplish this, they devised a technology called N-terminomics, which uses the peptide ligase called subtiligase. Subtiligase ligates peptide esters to the N-terminus of a protein or a peptide. This enzyme can be used for other purposes, such as peptide cyclization and protein bioconjugation. The lab used peptides tagged with biotin or fluorescently labelled in conjunction with mass spectrometry to identify sites of proteolytic cleavage.[2,3] Prof. Wells showed an example of this strategy used to identify sites of cleavage by caspase in the proteome of a human cell line in which apoptosis was induced. This approach, however, identified only a limited number of cleaved proteins. In the next implementation of the strategy, cells were directly transfected with subtiligase. This strategy allowed the identification of hundreds of extracellular proteins that were proteolytically modified.

The newest strategy invented in Prof. Wells’ lab (unpublished) involves tethering subtiligase to glycans of cell surface proteins instead of transacting cells. Using this latest strategy in Kras-transformed cells, 611 cell surface cleavage events were observed. In HER2-transfected cells, 267 cleavage events were observed and the majority of events were not related to cleavage of signal peptide from extracellular proteins. Interestingly, the extent of proteolytic modification of some proteins in oncogene-transformed cells can either increase or decrease. Similarly, expression levels of the same proteins also change in both directions. N-terminomics of Kras- and HER2-transformed cells was thus different.

This study also identified an interesting protein called CDCP1, which has cleavage and expression that is upregulated in pancreatic cancer. The cleavage is indeed specific to cancer cells. Three closely nested cleavage sites were found in CDCP1. Antibodies (CL03.2) were developed in the lab against the cleaved form  of CDCP1. Cells containing the cleaved form were efficiently killed by the anti-CDCP1 antibody formatted as an antibody-drug conjugate (ADC). In Jurkat cells, an anti-CD3/anti-CDCP1 bispecific single-chain variable fragment showed killing activity. For in vivo studies, mouse-specific antibodies toward the truncated form of CDCP1 were generated and used to produce an auristatin (MMAF)-based ADC. An ADC against the truncated form of CDCp1 was well tolerated in non-tumor-bearing mouse, but the animals lost weight when treated with an ADC targeting the full-length protein. In a study of mice bearing xenograph tumors, the animals were administered antibody against the truncated form that was radiolabeled with isotope Lu 177 and a dramatic decrease of tumor growth was observed.

[Read more…]

Filed Under: cancer Tagged With: Antibody drug conjugates, antibody therapeutics, bispecific, cancer

Tisotumab vedotin approved by FDA for cervical cancer

September 21, 2021 by Janice Reichert

On September 20, 2021, FDA granted accelerated approval to TIVDAK (tisotumab vedotin-tftv) for the treatment of adult patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy. The BLA for TIVDAK for this indication was given a Priority review. TIVDAK’s approval was based on tumor response and the durability of the response; verification and description of clinical benefit in confirmatory trials may be necessary for continued approval for this indication.

TIVDAK is an ADC comprising Genmab’s human tissue factor IgG1k antibody targeting tissue factor conjugated to MMAE via a protease-cleavable linker using Seagen’s ADC technology. The companies are co-developing the product. The recommended dose of TIVDAK is 2 mg/kg (up to a maximum of 200 mg) given as an intravenous infusion over 30 minutes every 3 weeks until disease progression or unacceptable toxicity.

FDA’s approval was based on results of the pivotal single-arm Phase 2 innovaTV 204 study (NCT03438396), which included 101 patients with recurrent or metastatic cervical cancer who had received no more than two prior systemic regimens in the recurrent or metastatic setting, including at least one prior platinum-based chemotherapy regimen. Patients received tisotumab vedotin 2.0 mg/kg IV every 3 weeks  until progression or toxicity. The major efficacy outcome measures were confirmed objective response rate as assessed by an independent review committee using RECIST v1.1 criteria and duration of response (DOR). The objective response rate was 24% [95% CI: 15.9%-33.3%], including 7 patients (7%) with a complete response and 17 patients (17%) with a partial response, and the median DOR was 8.3 months (95% CI: 4.2, not reached).

TIVDAK is the 9th antibody therapeutic to be first approved for marketing in the EU or US in 2021. Explore our searchable table of antibody therapeutics approved in the US or EU for details.

Filed Under: Antibody therapeutic, Antibody-drug conjugate, Approvals, Food and Drug Administration Tagged With: Antibody drug conjugates, antibody therapeutics, approved antibodies, Food and Drug Administration

FDA grants first approval to belantamab mafodotin-blmf

August 7, 2020 by Janice Reichert

On August 5, 2020, the U.S. Food and Drug Administration (FDA) approved belantamab mafodotin-blmf (BLENREP) for the treatment of adult patients with relapsed or refractory multiple myeloma who have received at least 4 prior therapies including an anti-CD38 monoclonal antibody, a proteasome inhibitor, and an immunomodulatory agent. BLENREP was granted an accelerated approval for this indication based on response rate. Further adequate and well-controlled studies/clinical trials must be done to verify and describe clinical benefit.

Belantamab mafodotin-blmf is an antibody-drug conjugate (ADC) composed of a humanized IgG1 monoclonal antibody and the cytotoxic agent maleimidocaproyl monomethyl auristatin F. The ADC binds to B-cell maturation antigen found on myeloma cell surfaces and is internalized. In the cell, the cytotoxic agent is released and kills the cells.

Belantamab mafodotin-blmf was evaluated in the Phase 2 DREAMM-2 (NCT03525678), an open-label, multicenter trial. Efficacy was based on overall response rate (ORR) and response duration. In patients receiving the recommended dose of 2.5 mg/kg, the ORR was 31% (97.5% CI: 21%, 43%) 73% of responders had response durations ≥6 months. Detailed results of the study were published in The Lancet Oncology in February 2020.

On July 24, 2020, the European Medicines Agency’s (EMA) human medicines committee recommended granting a conditional marketing authorization in the European Union for Blenrep (belantamab mafodotin) to treat adult patients with relapsed and refractory multiple myeloma who no longer respond to treatment with an immunomodulatory agent, a proteasome inhibitor and a CD-38 monoclonal antibody. Blenrep was accepted in EMA’s PRIME scheme, and it was designated as an orphan medicinal product. EMA recommended a conditional marketing authorization, and this opinion was sent to the European Commission for the adoption of a decision on an EU-wide marketing authorization.

Antibodies to watch

Belantamab mafodotin-blmf is the 7th antibody therapeutic to be granted a first approval in the US or EU in 2020. The Antibody Society maintains a comprehensive table of approved monoclonal antibody therapeutics and those in regulatory review in the EU or US. The table, which is located in the Web Resources section of the Society’s website, can be downloaded in Excel format. Information about antibody therapeutics approved outside the US or EU can be found in the table notes.

Information about other antibody therapeutics that may enter regulatory review in 2020 can be found in ‘Antibodies to watch in 2020’.

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Filed Under: Antibody-drug conjugate, Food and Drug Administration Tagged With: Antibody drug conjugates, belantamab mafodotin, Food and Drug Administration

FDA approves sacituzumab govitecan (Trodelvy®) for triple-negative breast cancer

April 22, 2020 by Janice Reichert

On April 22, 2020, the US Food and Drug Administration (FDA) granted an accelerated approval to Trodelvy® (sacituzumab govitecan-hziy) for the treatment of patients with metastatic triple-negative breast cancer who received at least two prior treatments for metastatic disease. Sacituzumab govitecan is composed of an anti-TROP-2 humanized IgG1 antibody conjugated to the topoisomerase inhibitor SN38, which is the active metabolite of irinotecan.

The approval was based on the results of a clinical trial of 108 patients with metastatic triple-negative breast cancer who had received at least two prior treatments for metastatic disease. In this study, the overall response rate was 33.3%, with a median duration of response of 7.7 months. Of the patients who responded to treatment, 55.6% maintained their response for 6 or more months and 16.7% maintained their response for 12 or more months.

The accelerated approval program allows FDA to approve drugs for serious conditions to fill an unmet medical need based on a surrogate endpoint, i.e., a result that is reasonably likely to predict a clinical benefit to patients. Additional clinical trials are required to confirm Trodelvy’s clinical benefit, and the FDA can remove the drug from the market if the confirmatory trial does not show that the drug provides clinical benefit.

Filed Under: ADC, Approvals, Food and Drug Administration Tagged With: Antibody drug conjugates, Food and Drug Administration, sacituzumab govitecan

World ADC Award Winners Announced

October 11, 2019 by Janice Reichert

The Antibody Society congratulates the winners of World ADC Awards!

World ADC Awards showcases the innovation, leadership and devotion shown by the best companies, teams and individuals in the industry. Across 9 categories, the Awards recognized the extraordinary endeavours, teamwork and commercial acumen that has propelled the antibody-drug conjugate field to the forefront of cancer research today. The 6th Annual World ADC Awards Ceremony took place on the evening of Thursday October 10, 2019 at the Manchester Grand Hyatt, San Diego. The finalists and winners were shortlisted from over 1,147 votes cast, and scientific proposals from each submission were evaluated by the Judging panel.

The 2019 winners are:

Best ADC Platform Technology

Zymeworks (ZymeLink) – Winner
LegoChem Bio (Scaffold Based Approach) – Runner Up

Best New Drug Developer

ADC Therapeutics – Winner
Zymeworks – Runner Up

Most Promising Clinical Candidate

Trastuzumab Deruxtecan (DS-8201a) – Winner
Enfortumab Vedotin (Seattle Genetics/Astella) – Runner Up

Best Contract Manufacturing Provider

BSP Pharmaceuticals – Winner
Millipore Sigma – Runner Up

Best Contract Research Provider

PPD – Winner
Abzena – Runner Up

Best Pre-Clinical Publication

Winner: Chemically triggered drug release from an antibody-drug conjugate leads to potent antitumour activity in mice. Rossin R, Versteegen RM, Wu J, Khasanov A, Wessels HJ, Steenbergen EJ, Ten Hoeve W, Janssen HM, van Onzen AHAM, Hudson PJ, Robillard MS. Nat Commun. 2018 May 4;9(1):1484.

Runner Up: Chemically Defined Antibody- and Small Molecule-Drug Conjugates for in Vivo Tumor Targeting Applications: A Comparative Analysis. Cazzamalli S, Dal Corso A, Widmayer F, Neri D. J Am Chem Soc. 2018 Feb 7;140(5):1617-1621.

Best Clinical Publication

Winner: Brentuximab Vedotin with Chemotherapy for Stage III or IV Hodgkin’s Lymphoma. Connors JM, Jurczak W, Straus DJ, Ansell SM, Kim WS, Gallamini A, Younes A, Alekseev S, Illés Á, Picardi M, Lech-Maranda E, Oki Y, Feldman T, Smolewski P, Savage KJ, Bartlett NL, Walewski J, Chen R, Ramchandren R, Zinzani PL, Cunningham D, Rosta A, Josephson NC, Song E, Sachs J, Liu R, Jolin HA, Huebner D, Radford J; ECHELON-1 Study Group. N Engl J Med. 2018 Jan 25;378(4):331-344. doi: 10.1056/NEJMoa1708984.

Individual Input to the Field 2018

Prof. Dario Neri  (ETH Zurich)

Long-Standing Contribution to the Field

Dr. Alain Beck (Pierre Fabre)

For more information about the World ADC Awards, visit http://worldadc-awards.com/

For more information about the World ADC San Diego conference, visit https://worldadc-usa.com/

Filed Under: ADC, Award for Excellence, Meetings Tagged With: ADC, Antibody drug conjugates

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