Bert Tighe, BS2 1 Compass Therapeutics, Cambridge, MA, USA; 2Compass Therapeutics LLC, Cambridge, MA, USA Correspondence: Robert Tighe ([email protected]) Journal for ImmunoTherapy of Cancer 2018, six(Suppl 1):PJournal for ImmunoTherapy of Cancer 2018, six(Suppl 1):Page 212 ofBackground CD137 (4-1BB) is usually a member with the TNFR superfamily that supplies costimulatory signals to activated cytotoxic lymphocytes. Agonistic antibodies against CD137 have shown promising therapeutic activity in mouse tumor models. However, hepatic toxicity has been observed in animals and humans with a couple of antiCD137 antibodies [1,2]. Recent advances in our understanding of TNFR Phospholipase Accession agonist antibodies implicate epitope, affinity, and IgG subclass as crucial contributors to function [3,4]. Here we describe the preclinical characterization of CTX-471, a totally human IgG4 agonist of CD137 having a differentiated pharmacology and toxicology profile. Solutions CTX-471 was identified determined by epitope binning and antigenbinding assays. The in vitro bioactivity of CTX-471 was measured inside a human IFN- release assay. The in vivo efficacy of CTX-471 was assessed in several syngeneic mouse tumor models that integrated various mechanistic endpoints: FACS evaluation of TILs, effector cell depletion, tumor histology, and Fc receptor profiling. The efficacy of CTX-471 was further evaluated in mice bearing quite large ( 500 mm3) CT26 tumors. Finally, the toxicity profile of CTX-471 was evaluated in mice and cynomolgus monkeys. Final results CTX-471 binds to a exceptional epitope shared by human, cynomolgus monkey, and mouse CD137. In vitro, CTX-471 improved IFN- production by human T cells in an FcR-dependent manner, displaying an intermediate level of activity between two clinical-stage anti-CD137 antibodies. In Vivo, CTX-471 exhibited curative monotherapy activity in CT26, A20, and EMT-6 models. When compared to known anti-CD137, OX-40, PD-1, PD-L1, and CTLA-4 antibodies, only an affinity-optimized version of CTX-471 showed the ability to eradicate pretty substantial tumors. All mice cured by CTX-471 rejected tumors upon rechallenge. CTX-471 profoundly reprogramed the TME, major to an influx of inflammatory cells, decreased T cell exhaustion, Treg depletion, and TAM modulation, although having incredibly little effect on the peripheral immune technique. Tumor models with abundant expression of FcR’s responded a lot more strongly to CTX-471 treatment, and Fc Toll-like Receptor (TLR) Inhibitor Compound silencing mutations attenuated efficacy. In mice and monkeys, really high doses of CTX-471 (up to 100 mg/kg weekly for 4 weeks) were welltolerated, with no signs of hepatic toxicity. Conclusions CTX-471 displays a favorable and well-differentiated efficacy-safety profile that’s attributed to a exclusive epitope, optimized affinity, and FcR-dependent activity. To our knowledge, CTX-471’s level of monotherapy efficacy against pretty substantial tumors is unprecedented for an IO antibody. IND-enabling toxicology studies are underway, plus a Phase 1 trial is planned for the first-half of 2019.References 1. Bartkowiak T, Jaiswal AR, Ager CR, et al. Activation of 4-1BB on liver myeloid cells triggers hepatitis by means of an interleukin-27 ependent pathway. Clinical Cancer Research. 2018 Apr;24(five):11381. 2. Segal NH, Logan TF, Hodi FS, et al. Benefits from an integrated security analysis of urelumab, an agonist Anti- CD137 monoclonal antibody. Clinical Cancer Research. 2016;23(8):19296. 3. Yu X, Chan HTC, Orr CM, et al. Complex interplay in between epitope specificity and isotype di.
