Reference Detail

Ref Type

PMID

Authors

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 and Sanjeev Redkar

Title

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

Journal	Vol	Issue	Date	Pages	Journal Short Title
			2018

URL

https://mct.aacrjournals.org/content/17/1_Supplement/A200

Abstract Text

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.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References