CBT-502: A Promising Anti-PD-L1 Antibody with Potent Antitumor Activity in Preclinical Cancer Models

CBT-502 (TQB2450) is a distinctive humanized IgG1 antibody that targets the programmed cell death-ligand 1 (PD-L1), with substantial sequence divergence in complementarity-determining regions (CDRs) compared to existing anti-PD-L1 antibodies such as atezolizumab, durvalumab, and avelumab. PD-L1's expression is notably high in various human cancer cells and plays a critical role in inhibiting cytotoxic T cells by binding to PD-1 and CD80. The therapeutic blockade of PD-L1 has been shown to reduce tumor growth when immune cells are present.

In vitro studies have confirmed CBT-502's high binding affinity to human PD-L1, with a dissociation constant (KD) of 0.25 nM as measured by surface plasmon resonance (SPR). The antibody effectively prevents the interaction between human PD-1 and PD-L1, with an IC50 of 47.97 pM, and also inhibits PD-L1's binding to CD80 with an IC50 of 1.09 nM. CBT-502 has been shown to robustly activate T cells, as evidenced by IFN-gamma production in a mixed lymphocyte reaction assay.

Pharmacokinetic studies in cynomologus monkeys have demonstrated a linear dose-dependent relationship for CBT-502. The antibody has shown no affinity for Fc receptors, including FcgRIa, FcgRIIa-167His/Arg, FcgRIIIa-176Phe/Val, FcRn, and C1Q, as determined by SPR. In toxicology screens, no adverse effects were observed at a no-observed-adverse-effect-level (NOAEL) of 200 mg/kg.

In vivo antitumor activity of CBT-502 was assessed in two mouse models: A375 (melanoma) and MC-38/H-11 (colon cancer). In the MC-38/H-11 model, CBT-502 showed comparable tumor growth inhibition (TGI) rates to atezolizumab at a dose of 15 mg/kg. In the A375 model, CBT-502 exhibited potent dose-dependent antitumor activity, with TGI percentages of 53.5% at 10 mg/kg administered three times weekly, compared to 59.4% for atezolizumab at the same dosage. Notably, CBT-502 did not lead to significant body weight loss, unlike atezolizumab which caused a slight reduction at 10 mg/kg three times weekly.

The preclinical pharmacodynamics and toxicology studies indicate that CBT-502 has pharmacological activity and is well tolerated at effective doses, offering a wide safety margin. The in vivo efficacy and safety data in the A375 model were favorable when compared to atezolizumab, and the MC38 model confirmed the activity of CBT-502. Based on these promising nonclinical data, CBT Pharmaceuticals and their China partner CTTQ are planning to develop and evaluate CBT-502 in multiple solid tumors.

The research was presented by Zhao Wei, Ling Yang, and colleagues at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics in 2017.