新型PD-1xVEGFxIL-2三特异性免疫调节剂具有更优的安全性和更强的疗效

PD-1 antagonist antibodies have demonstrated significant success in the clinic. However, low response rate and high cancer recurrence requires the development of next-generation immunotherapies. Bispecific immune modulators PD-1xVEGF and PD-1xIL-2 molecules have shown promising clinical improvement over PD-1 antagonist antibodies, particularly in populations resistant to PD-1 monotherapy. VEGF, a soluble dimer enriched in the tumor microenvironment (TME), plays a crucial role in angiogenesis and tumor growth. Local enrichment of PD-1xVEGF bispecific antibodies by VEGF dimers could further potentiate the efficacy of PD-1 blockade. On the other hand, IL-2 of PD-1xIL-2 molecules can be cis-presented on PD-1-expressing T cells, expanding tumor-specific T cell populations and enhancing the functions of PD-1 antibodies. We therefore built a novel PD-1xVEGFxIL-2 trispecific immune modulator that combines the biologic functions of all three. We have optimized the trispecific format to retain the affinity and potency of both VEGF and PD-1 blockers. The proprietary IL-2 mutein has over 1000X attenuated IL-2Rbetagamma binding and muted CD25 binding to ameliorate systemic immunotoxicity on non-specific T and NK cells in the periphery. The sub-nanomolar anti-PD-1 antibody then directs IL-2 mutein to PD-1+ T cells and effectively replaces the natural function of CD25. Thus, proprietary IL-2 mutein specifically acts on PD-1-expressing tumor-specific T cells to expand effector populations. VEGF neutralization suppresses angiogenesis and potentiates the potency of PD-1 blockade. These creates a “super PD-1” next-generation immune modulator. PD-1xVEGFxIL-2 trispecific has been fully characterized. The potency of the trispecific for PD-1 and VEGF blockades were comparable to the respective monoclonal antibodies. The proprietary IL-2 mutein bound weakly to human IL-2Rbetagamma, with equivalent affinity to cynomolgus and mouse IL-2Rbetagamma. This IL-2 variant was inert on primary pan T cells and did not activate Treg cells, but induced potent activation of PD-1+ T cells. In addition, PD-1xVEGFxIL-2 enhanced immune activation of T cells induced by A375 tumor cells in a co-culture system. In an exploratory toxicity study, the attenuated IL-2 mutein supported a higher maximum tolerated dose for the trispecific than IBI363 in cynomolgus monkeys, which matched the optimal therapeutic doses for PD-1 and PD-1xVEGF antibodies. In mouse efficacy studies, PD-1xVEGFxIL-2 exhibited significantly greater efficacy than both PD-1xVEGF and PD-1xIL-2 in PBMC-engrafted CDX model and mouse syngeneic models. In summary, WuXi Biologics has developed a novel PD-1xVEGFxIL-2 trispecific molecule. This potent next-generation immune modulator shows great potential for further clinical investigation.