Development of a unique anti-CD137 therapeutic antibody: Efficacy and safety profiles in mono and combination therapy.

Abstract

e23079 Background: Abstract: CD137 (4-1BB), a member of the TNFR super family, is expressed on several subsets of activated immune cells and acts as co-stimulatory receptor for T-cells to promote cellular proliferation, survival and cytokine production. Agonist antibodies against human CD137 in early clinical trials show strikingly different toxicology profiles, ranging from severe liver toxicity at low doses, to manageable adverse effects at modest doses. Whereas preclinical studies in mouse show intense liver T-cell infiltration and toxicity by surrogate agonist mAb. The preclinical efficacy and pharmacology of anti-CD137 were extensively tested and validated in various tumor models with intact immune system. Since none of the available anti-CD137 agonist antibodies display multiple species cross reactivity including rodent, the translational significance of these mAbs is limited concerning their efficacy and safety profile. Methods: Through our proprietary Dynamic Precision Library (DPL) technology, we have discovered multiple agonistic antibodies that exhibit high affinity and broad species cross-reactivity against a unique epitope shared among human, monkey and rodent CD137. Results: These mAbs, after crosslinking, strongly activate CD137 mediated cellular NFkB signaling, as well as stimulate T-cell proliferation and IFNg release in the presence of suboptimal concentrations of anti-CD3 antibodies. The broad species cross-reactivity by a single therapeutic agent enabled us to evaluate their potentiation of host immune responses that gives rise to the anti-tumor efficacy and potential toxicity in relevant rodent and monkey models. Our lead anti-CD137 agonist mAb has demonstrated robust anti-tumor activities in multiple mouse syngeneic tumor models, with durable antigen specific protective memory T-cell responses. Conclusions: In sharp contrast to surrogate anti-mouse CD137 mAbs, no toxicities including liver inflammation or other adverse effects were observed. These preclinical results warrant further clinical development of our lead as a novel immunotherapeutic anti-cancer agent.