145P - An Engineered Ligand-Trap Biologic Targeting the CD47 Signaling Pathway for Cancer Treatment with Superb Efficacy and Safety Profiles

Background

Macrophages exert their functions mainly through SIRPa receptor, which interacts with CD47 on cellular targets. As many cancer cells overexpress CD47 to evade immune surveillance, blocking SIRPa-CD47 interaction represents a promising approach to control tumor progression. The clinical progress of anti-CD47 antibodies were hindered by either side effects or lacking appreciable efficacy. To overcome this dilemma, we engineered a SIRPa-fusion protein that exhibits superior efficacy against multiple tumor types while maintaining good safety profiles.

Methods

Using structure-guided protein engineering, we selected a SIRPa mutant that exhibited marked phagocytic abilities against tumors while maintaining good safety features on normal cells. To assess the efficacy of this molecule, it was tested in multiple xenograft mouse models alongside competing biologics currently in clinical trials. We also performed quantitative RNA transcriptional analysis to evaluate the changes in gene expression inside tumor and in the tumor microenvironment.

Results

Comparing to other clinical candidates, HCB101 triggered strong phagocytic reactions against tumor cells but not red blood cells. We have analyzed 14 human tumor xenograft models, HCB101 consistently showed excellent efficacy against heme and solid tumors, with tumor growth inhibition index ranging from 60-100% at the dose of 0.5-10mg/kg over placebo. We also observed an increase in M1/M2 macrophage ratio after the treatment with HCB101, which correlated with the observed anti-tumor efficacy. Quantitative RNA transcriptional analysis indicated that HCB101 triggered drastic changes in gene expression comparing to other competing molecules. This suggested a unique MOA underlying HCB101’s superior efficacy. There was no apparent adverse reaction observed during the toxicology studies, indicating a good safety profile.

Conclusions

Comparing to relevant clinical candidates, HCB101 exhibits superior efficacy in 14 different CDX models of hemotological and solid tumors while maintaining good safety profiles. It is a highly effective biologic with robust efficacy, both as monotherapy and in combination. Clinical trial of HCB101 is now in progress.

Clinical trial identification

NCT05892718.

Legal entity responsible for the study

HanchorBio, Inc.

Funding

HanchorBio, Inc.

Disclosure

All authors have declared no conflicts of interest.