Checkpoint Modulators and Combination Therapies for Cancer

Checkpoints are molecular blockers or promoters, depending on the circumstances, that prevent the immune system from attacking the body’s own normal tissue. As you probably know, when these systems fail, an individual can develop autoimmune diseases such as rheumatoid arthritis and MS. One of the challenges with cancers is that as they advance, they learn to escape immune destruction by taking advantage of these checkpoint mechanisms for their protection.

In March 2011, Bristol-Myers Squibb’s Yervoy® (ipilimumab, a CTLA-4 antagonist) was the first antibody CPM (check point modulator) approved for the treatment of metastatic melanoma. There is now a rapidly expanding list of CPMs in various stages of development.  These agents have shown unprecedented efficacy and, presently, they constitute the most promising tools for successfully combating cancer.

Today, at Agenus, we have a number of immune checkpoint antibody programs directed at six checkpoint targets, including clinically validated targets such as CTLA-4 and PD-1. In addition, we have four additional novel target programs, which include GITR, OX40, LAG-3 and TIM-3. Some of these targets may have utility beyond cancer. We plan to advance our CPMs both as single agents as well as in combinations, including potential combinations with other anti-cancer agents for which there is strong rationale for synergistic effects with CPMs.

At ASCO last year, there were clear indications of the improved effect in cancer patients where combination checkpoint antibodies were used. For example, when ipilimumab was combined with nivolumab in advanced melanoma patients, responses doubled as compared to ipilimumab alone. At this year’s ASCO, we expect much more on this subject including the compelling rationale of combinations of checkpoint therapies to treat cancer. There is no doubt that combinations will be the cornerstone of future CPM development strategies, and given the substantial number of checkpoint programs we have at Agenus, we look forward to participating in this field.

Exciting new insights emerging from translational research may position us to assess whether CPMs may have potential therapeutic activity long before clinical efficacy signals emerge. Our collaboration with our translational medicine partner, Ludwig Cancer Research (LCR), allows us the benefit of such early readouts, which may be useful surrogates of clinical benefit.

While we are amongst the smaller companies facing the giants in the checkpoint space, our Retrocyte Display® technology platform offers us the ability for discovering and optimizing fully-human antibodies against a wide array of molecular targets. This platform has unique advantages because it uses B cells to generate antibody candidates. The main benefit of utilizing B cells compared with techniques that rely on bacterial systems to generate antibodies is that B cells are the natural factories for producing therapeutic antibodies. By employing B cells, we are using a system which has been optimized through evolution over many millions of years to produce antibody molecules that are active in the human body. We believe our proprietary platform has the potential to generate best-in-class immunotherapies.

This point was recently validated by the recent announcement of our collaboration with Merck. We are working with Merck on two of their novel checkpoint targets for cancer immunotherapy and this broadens our efforts in this field. Merck has become a key player in the rapidly developing immuno-oncology space and this agreement highlights our Retrocyte Display® platform’s ability for the discovery of a wide array of diverse checkpoint antibodies.

As the exciting field of immuno-oncology delivers on its expected promise, we look forward to advancing our programs. We anticipate that we will be filing one or more Investigational New Drug Applications for a CPM program in 2015, and we are targeting to enter human clinical studies in 2016. We look forward to sharing updates as we make progress in these areas.

Robert F. Burns, PhD


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Dr. Burns serves as President of 4-Antibody AG and guides Agenus' collaborations with leading academic centres as the Chairman of the Scientific Advisory Board.

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