Abstract A200: CBT-502 (TQB2450), a novel anti-PD-L1 antibody, demonstrates favorable activity in MC-38/H-11 murine colon and A375 human melanoma animal models
Authors: Wei Zhao , Yang Ling , Li Yingchun , Lu Jiansheng , Zhang Xiquan , Tian Xin , Zha Jiping , Sun Ziyong , Qiu Junzhuan , Wang Zhun , Reddy Mamatha , Choy Gavin S. , Redkar Sanjeev 
Published: August 2018

Abstract
Background: CBT-502 (TQB2450) is a novel humanized IgG1 antibody against programmed cell death-ligand 1(PD-L1) developed by CBT Pharmaceuticals, Inc. CBT-502 shows significant sequence divergence in CDRs from other anti-PD-L1 antibodies in the market today, including atezolizumab, durvalumab, and avelumab. Several human cancer cells express high levels of PD-L1. PD-L1 binds to its receptor, PD-1, on activated T cells, and CD80, on dendritic cells and monocytes and inhibits cytotoxic T cells. Therapeutic blockade of PD-L1 reduces the growth of tumors in the presence of immune cells. In vitro, CBT-502 demonstrated binding affinity to human PD-L1 by SPR of 0.25 nM and cyno-PD-L1 of 0.24 nM. In cell based assay, CBT-502 effectively blocked the interaction of hPD-1 and hPD-L1 (IC50 47.97 pM) and blocked binding of PD-L1 with CD80 (IC50 1.09 nM). CBT-502 strongly activates T cells as measured by IFN-gamma production in a mixed lymphocyte reaction assay. Pharmacokinetic data in cynomologus monkeys showed a linear dose-dependent relationship. No adverse clinical or histopathologic findings were observed in toxicology screen (NOAEL=200 mg/kg). CBT-502 showed no Fc receptor affinity including FcgRIa, FcgRIIa-167His/Arg, FcgRIIIa-176Phe/Val, FcRn SPR and C1Q. In vivo antitumor activity was evaluated in two mouse models, A375 (melanoma) and MC-38/H-11 (colon), reported herein. Methods: Fifty C57BL/6 mice were intraperitoneally (IP) inoculated with 1x105 MC-38/H-11 cells, and the mice were randomly divided into five groups on Day 2 (D0) following inoculation. The test article group was intraperitoneally injected (IP) with 1.5, 5 and 15 mg/kg once every other day (Q2D) x 11 times while the positive control group (atezolizumab) was administered IP with 15 mg/kg, and the negative control group (human IgG) was injected with same volume at 15 mg/kg. Similarly, A375 human melanoma cells (5 x 106) were implanted subcutaneously in the flank region of highly immune-deficient mouse model (NCG mouse, n=36). The mouse immune system was replaced with human PBMC. Only mice with high CD45 ratio are included in the study. CBT-502 was dosed IP at 5 and 10 mg/kg once weekly (qw) and three times weekly (tiw), whereas atezolizumab was dosed 10 mg/kg (tiw). Results: In the MC-38/H-11 model, CBT-502 relative to atezolizumab demonstrated comparable tumor growth inhibition (TGI) rates, 91.7% vs. 93.8% in the 15 mg/kg dose group. CBT-502 showed potent in vivo antitumor activity in a dose-dependent manner in the A375 model. TGI % at 10 mg/kg tiw was 53.5% and 59.4% for CBT-502 and atezolizumab, respectively. There was no obvious loss of body weight (BW) with CBT-502 administration, although a slight reduction in BW was observed with atezolizumab 10 mg/kg tiw. Conclusions: CBT-502 preclinical pharmacodynamics and toxicology studies demonstrated pharmacologic activity and is well tolerated at effective doses with a wide margin of safety. In vivo efficacy and safety data in the A375 model compared favorably to atezolizumab, with the MC38 model confirming activity of CBT-502. With these encouraging nonclinical data, CBT Pharmaceuticals and China partner CTTQ plan to develop and evaluate CBT-502 in multiple solid tumors, anticipated in 2018.
Citation Format: Zhao Wei, Ling Yang, Yingchun Li, Jiansheng Lu, Xiquan Zhang, Xin Tian, Jiping Zha, Ziyong Sun, Junzhuan Qiu, Zhun Wang, Mamatha Reddy, Gavin S. Choy, Sanjeev Redkar. CBT-502 (TQB2450), a novel anti-PD-L1 antibody, demonstrates favorable activity in MC-38/H-11 murine colon and A375 human melanoma animal models [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A200.