It is an intriguing approach to target the ecto-5'-nucleotidase CD73 to confer synergetic beneficial survival in cancer patients, along with clinically established immunotherapy targets. In this study, a fully human, subnanomolar affinity CD73 antibody IBI325 was developed using the yeast display platform. Compared with Oleclumab, IBI325 was equivalent in hCD73 affinity and more potent in cell-bound and soluble CD73 enzymatic inhibition, and no hook effects were observed. Correspondingly, adenosine monophosphate-mediated immune suppression was reversed by IBI325, and significant T cell proliferation and release of cytokines were observed. Also, IBI325 enhanced the T cell recall response by inducing interferon-γ secretion. The antitumor efficacy of IBI325 was investigated in a hPBMC-reconstituted NOG mouse model, and a hCD73 knock-in mouse model. Consequently, IBI325 induced a significant tumor regression by inducing intratumoral immune cell expansion, and a combo therapy of IBI325 and aPD-1 was superior in efficacy than aCD73 or aPD-1 monotherapy. Additionally, the binding epitopes of CD73 to IBI325 were distinct from previously reported aCD73 therapeutics. IBI325 displayed acceptable pharmacokinetics and sufficient tolerable safety profiles to support clinical development. In conclusion, the pharmacology, pharmacokinetics, and toxicity profiles of IBI325 with complete CD73 inhibition were characterized, and encouraging preclinical outcomes were reported.
Keywords: CD73 antagonist; Cancer immunotherapy; IBI325; Therapeutic antibody.
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