David_SzymkowskiDr. David Szymkowski recently shared insight on his upcoming presentation "Bispecific Antibodies for Dual Immune Checkpoint Blockade" to be delivered at the 7th Annual Bispecific Antibody Therapeutics conference, taking place January 10-11, 2017 as part of the 16th Annual PepTalk event which runs from January 11-12, 2018 in San Diego, CA.

Bispecific Antibody Therapeutics Conference Presentation

Part of PepTalk 2018

Thursday, January 11 | 2:35 pm

Bispecific Antibodies for Dual Immune Checkpoint Blockade

Combinations of checkpoint-blocking antibodies are more efficacious then single inhibitors, but generate greater immune-related toxicities. We reasoned that a bispecific antibody could achieve dual blockade to selectively target tumor-reactive lymphocytes, improving safety and efficacy. We generated multiple dual-checkpoint inhibitors including XmAb20717 (anti-PD1 x anti-CTLA4) that display compelling in vivo activity relative to combinations of monospecific antibodies, suggesting that checkpoint bispecifics may have clinical advantages for the treatment of cancer.

Q. What are the potential advantages of checkpoint-blocking bispecific antibodies vs. traditional combination therapies?

After many years of false starts, our industry finally has a handle on how to manufacture bispecific and even multi-specific antibodies that can simultaneously engage two or more discrete targets. So, what can we do with these unique new molecules? We are now in the exciting phase of deciding how and where to apply such bispecifics in the clinic. The first wave (which I’m sure will continue for many more years) has been largely focused on T cell-engaging anti-tumor antibodies, but my company is among several believing that dual-checkpoint inhibitors will be the next big “killer app” for bispecifics. We already know that combinations of checkpoint inhibitors work better clinically than does CPI monotherapy, but with significantly increased toxiciy (not to mention cost). Given the success of combo CPIs, it is a reasonable hypothesis that a single bispecific antibody targeting two T cell checkpoints (i.e., selectively blocking only tumor-infiltrating T cells expressing multiple checkpoint targets) may show superior efficacy and safety compared to a conventional combination of two separate CPI antibodies.

Q. What are the drawbacks?

The primary drawback is that the superiority of a CPI bispecific compared to CPI combination therapy is only a hypothesis. That is, we know that individual checkpoint inhibitors are effective in a subset of patients, and we know that combinations are more effective yet more toxic… but the rationale for bispecific CPIs, even supported by good preclinical proof-of-concept data, still needs to be assessed in the clinic. Another big question is, what are the right checkpoint inhibitors to build into these bispecifics? Given their proven clinical efficacy individually and in combination, PD-1 and CTLA-4 are the obvious first choice, but what comes after that? Just as for monospecific CPIs, selecting the right bispecific pairs for clinical development will require good data from sophisticated human ex vivo, mouse, and even monkey models.

Q. What are you most looking forward to at PepTalk?

I especially enjoy PepTalk because it is such a large meeting covering every aspect of biologics R&D. I attend because PepTalk focuses more than most conferences on the nuts & bolts of antibody development – the protein engineering, manufacturing, and analytics – allowing me to catch up on the core “protein science” underlying the next generation of biotherapeutics. Besides the tools, there is still plenty of new material on interesting targets, and updates on biologics moving into clinical development. The smaller dinner courses and training sessions are also a useful setting conducive to networking and discussion – no worries about “dumb questions” in those. The exhibit hall at PepTalk is also a good opportunity for those of us in research to check out the latest instruments and technologies.

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