Shanghai, China, October 24th, 2023 – Shanghai Henlius Biotech, Inc. (2696. HK) announced that the results from the preclinical study of HLX42, the novel EGFR targeting ADC which was developed by the company based on the collaboration with MediLink Therapeutics was released as poster at the 2023 European Society of Medical Oncology (ESMO) Congress.

Despite the great success of monoclonal antibody targeting EGFR and 3rd generation EGFR TKIs, there is still a significant unmet medical need for effective therapies for patients who are refractory to current therapies or relapse after standard of care. The EGFR-targeting ADC has the potential to overcome the resistance to EGFR monoclonal antibodies and Tyrosine kinase inhibitors (TKIs), which may bring additional clinical benefits to patients who are resistant or refractory to EGFR targeted therapy^[1]. HLX42 is a novel EGFR-targeting ADC, comprised of a high-affinity humanized IgG1 antibody targeting EGFR, conjugated with a novel topoisomerase-I inhibitor payload, the drug to antibody ratio (DAR) is around 8. The linker-payload will be cleaved and released in tumour microenvironment(TME) with strong bystander killing effects. This unique mechanism of TME activation and payload release allows HLX42 to possess a higher therapeutic index and potency for treatment of solid tumours^[2]. In August 2023, the investigational new drug (IND) application of HLX42 was accepted for review by the National Medical Products Administration (NMPA) of China.

Title

Preclinical evaluation of HLX42, a novel EGFR-targeting ADC, for Cetuximab or TKI resistant cancer.

Methods

HLX42 was examined in antigen binding, internalisation and plasma stability assays; efficacy analyses were performed in CDX and PDX models including HT-29, NCI-H1993, EBC-1, and LU3075, etc.

Results

In vitro analyses demonstrated that HLX42 possessed similar affinity and internalisation rate compared to parental antibody, and it was stable in the plasma of rats and cynomolgus monkeys.

In in vivo studies, HLX42 showed potent tumour suppression in several CDX and PDX models that were cetuximab or TKIs resistant. As in the HT-29 model, weekly administration of HLX42 at 8 mg/kg for 3 weeks resulted in 90.2% TGI. Likewise, HLX42 showed better in vivo efficacy and elicited more durable antitumour responses in a head-to-head comparison with conventional ADC technologies such as VC-MMAE. In the NCI-H1993 model, weekly administration of HLX42 at 8 mg/kg for 3 weeks resulted in 91.5% TGI compared to 79.8% TGI when treated with anti-EGFR Ab-GGFG-Dxd. Similarly, in the EBC-1 model, weekly administration of HLX42 at 8 mg/kg for 3 weeks eradicated all lesions; all mice remained tumour free three weeks after the last dose, while tumour began to regrow in the anti-EGFR Ab-VC-MMAE treated group. HLX42, combined with a 3rd generation TKI, showed strong synergy in the LU3075 PDX model which poorly responded to Osimertinib monotherapy in the same experiment. In another NSCLC PDX model harboring EGFR exon19 deletion/T790M/C797S mutations, which exhibited complete resistance to Osimertinib. A single dose treatment resulted in significantly complete response. In our pilot toxicity studies conducted in rats and cynomolgus monkeys, HLX42 demonstrated good safety profiles in both species.

Conclusion

Taken together, these preclinical data strongly suggest that HLX42 is a potential best-in-class EGFR-targeting ADC which is worth further clinical investigations.

参考文献

[1] Tan C S, Gilligan D, Pacey S. Treatment approaches for EGFR-inhibitor-resistant patients with non-small-cell lung cancer[J].The Lancet Oncology,2015,16(9) 

[2] ]Jiaqiang C, Shuai S, Qing Z, et al; Abstract 596: Development and assessment of a novel tumor microenvironment activable linker (TMALIN) ADC platform for solid tumor treatments. Cancer Res 1 April 2023; 83 (7_Supplement): 596.