On March 5, 2014 Ludwig Cancer Research and Agenus reported the selection of three monoclonal antibody checkpoint modulators (CPMs) that Agenus is advancing into preclinical development (Press release Agenus, MAR 5, 2014, View Source [SID:1234500847]). These product candidates—two GITR agonists and a CTLA-4 antagonist—target cell-surface checkpoint proteins that control immune responses. They are part of Agenus’ recent acquisition of 4-Antibody AG and the result of several years of intensive collaborative efforts between 4-Antibody and Ludwig Cancer Research. The parties also have ongoing programs to discover and develop other immune checkpoint modulator antibodies, including OX40 agonists and antagonists of LAG-3, TIM-3 and PD-1.

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"GITR, a checkpoint protein on T-lymphocytes, plays an important role in amplifying specific cellular immune responses, including those against tumors. We are encouraged to have identified high-quality agonist antibodies for this very competitive target, something that has proven difficult for many other companies," said Robert B. Stein, MD, PhD, Chief Scientific Officer of Agenus. "Furthermore, it is rational to combine CPMs such as CTLA-4 and PD-1 antagonists with anti-cancer vaccines, and we are collaborating on an on-going Phase 2 trial exploring Prophage and Yervoy (CTLA-4 antagonist) in patients with metastatic melanoma. Intelligently designed translational studies may improve the odds of success for our CPMs and accelerate their clinical development."

In collaboration with its translational research partner Ludwig Cancer Research, Agenus and 4-Antibody plan to advance the emerging portfolio of CPMs as single agents and in optimized combinations, including potential combinations with the company’s anti-cancer vaccine and other agents.

"The Retrocyte Display1 technology developed by 4-Antibody over the last decade has allowed us to create attractive CPM antibodies directed against key checkpoint targets," said Robert Burns, PhD, CEO of 4-Antibody. "By combining our know-how with Agenus’ immunotherapy development expertise, we expect to propel these candidates through preclinical and clinical development."

"The collaboration with 4-Antibody allowed us to rapidly advance antibodies into development," said Jonathan Skipper, Ludwig’s Executive Director of Technology Development. "We are now planning clinical studies to evaluate novel combinations of these antibodies. Ludwig has been at the forefront of translational research in immuno-oncology for several decades. Our ongoing relationship with Agenus is a good example of our broader strategy to advance cancer therapy."

CPMs like CTLA-4 and PD-1 antagonists make cancer more vulnerable to immune attack by releasing the brakes on the anti-cancer immune response and neutralizing the defenses cancer cells use to fend off that attack. Cancer vaccines, meanwhile, are designed to enhance the immune system’s recognition of cancer cells as abnormal based on mutant proteins that they display. Scientists reason that, together, these strategies should deliver a one-two punch against cancer that could have a durable therapeutic impact.