A study on the efficacy and Safety Evaluation of a novel PD-1/CTLA-4 bispecific antibody
Qi Song1, Meiling Jiang2, Xinrong Pan2
1Department of Pharmacology, SanHome, Nanjing, PR China; College of Life Science and Technology, China Pharmaceutical University, Nanjing, PR China.
Abstract:
Tumors constitute a significant health concern for humans, and PD-1 and CTLA-4 monoclonal antibodies have been proven effective in cancer treatment. Some researchers have identified that the combination of PD-1 and CTLA-4 dual blockade demonstrates superior therapeutic efficacy. However, the development of PD-1/CTLA-4 bispecific antibodies faces challenges in terms of both safety and efficacy. The present study discloses a novel PD-1/CTLA-4 bispecific antibody, designated as SH010. Experimental validation through surface plasmon resonance (SPR) confirmed that SH010 exhibits favorable binding activity with both PD-1 and CTLA-4. Flow cytometry analysis demonstrated stable binding of SH010 antibody to CHOK1 cells overexpressing human or cynomolgus monkey PD-1 protein and to 293F cells overexpressing human or cynomolgus monkey CTLA-4 protein. Moreover, it exhibited excellent blocking capabilities in protein binding between human PD-1 and PD-L1, as well as human CTLA-4 and CD80/CD86. Simultaneously, in vitro experiments indicate that SH010 exerts a significant activating effect on hPBMCs. In murine transplant models of human prostate cancer (22RV1) and small cell lung cancer (NCI-H69), administration of varying concentrations of the bispecific antibody significantly inhibits tumor growth. MSD analysis revealed that stimulation of hPBMCs from three different donors with SH010 did not induce the production of cytokine release syndrome. Furthermore, Single or repeated intravenous administrations of SH010 in cynomolgus monkeys show favorable systemic exposure without noticeable drug accumulation or apparent toxicity. In conclusion, SH010 represents a novel cancer therapeutic drug poised to enter clinical trials and obtain market approval.
Insights
A novel bispecific antibody, SH010, targeting PD-1 and CTLA-4, effectively inhibits tumor growth in preclinical models. SH010 demonstrates favorable safety and efficacy profiles, paving the way for clinical trials in cancer therapy.
Area of Science:
- Immunology
- Oncology
- Biotechnology
Background:
- Tumors pose a significant health challenge, with PD-1 and CTLA-4 antibodies showing promise in cancer treatment.
- Dual blockade of PD-1 and CTLA-4 offers superior therapeutic potential, but developing bispecific antibodies presents safety and efficacy challenges.
Purpose of the Study:
- To introduce and validate a novel PD-1/CTLA-4 bispecific antibody, SH010, for cancer therapy.
- To assess the binding activity, blocking capabilities, in vitro immune cell activation, in vivo anti-tumor efficacy, and safety profile of SH010.
Main Methods:
- Surface plasmon resonance (SPR) and flow cytometry were used to confirm binding activity.
- In vitro assays evaluated blocking of PD-1/PD-L1 and CTLA-4/CD80/CD86 interactions and T-cell activation.
- In vivo studies utilized murine transplant models, while safety was assessed in cynomolgus monkeys.
Main Results:
- SH010 demonstrated strong binding to PD-1 and CTLA-4 and effectively blocked their interactions.
- The antibody significantly inhibited tumor growth in prostate and small cell lung cancer models.
- SH010 showed no induction of cytokine release syndrome and favorable safety profiles in non-human primates.
Conclusions:
- SH010 is a promising novel bispecific antibody for cancer treatment.
- The antibody exhibits potent anti-tumor activity and a favorable safety profile.
- SH010 is a strong candidate for clinical trials and potential market approval.
