China NMPA approves Henlius’ IND applications of HLX42 & HLX43 to treat advance/metastatic solid tumours

Shanghai Henlius Biotech, Inc. announced that the investigational new drug (IND) applications of HLX42 for injection, a novel EGFR-targeting antibody-drug conjugate (ADC) as well as HLX43, a novel PD-L1-targeting ADC, have been approved by the National Medical Products Administration (NMPA), for the treatment of advance/metastatic solid tumours.

The two products were developed by the company based on the collaboration with MediLink Therapeutics and become first ADC candidates of Henlius that are entering into clinical development. Considering that there are few ADC candidates that targeting PD-L1, HLX43 is the first PD-L1-targeting ADC in China. Furthermore, there are still various ADC/AXC candidates in Henlius’ portfolio that are under preclinical development.

EGFR belongs to the receptor tyrosine kinases family and plays an important role in maintaining normal cell functions such as cell proliferation, differentiation and migration. Mutation or overexpression of EGFR is considered to be closely associated with the occurrence of various solid tumours including non-small cell lung cancer (NSCLC), colorectal cancer (CRC), etc. Studies have shown that targeting EGFR is a valid strategy for anticancer therapy. Despite the great success of monoclonal antibodies targeting EGFR and 3rd generation EGFR Tyrosine kinase inhibitors (TKIs), there are still great unmet medical needs for effective therapies for patients who are refractory to current therapies or relapse after standard of care. ADC technology has vastly advanced in the last several years and provide a new treatment option for tumour patients. The EGFR-targeting ADC has the potential to overcome the resistance to EGFR monoclonal antibodies and EGFR TKIs, which may bring clinical benefits to more patients with advanced NSCLC/CRC who are resistant or refractory to standard EGFR targeted therapy.

HLX42 is a novel EGFR-targeting ADC, comprised of a high-affinity humanised IgG1 mAb targeting EGFR conjugated with a novel cytotoxic payload through cleavable linkers, with the drug-to-antibody ratio is about 8. The cytotoxic payload is a novel DNA topoisomerase-I inhibitor which can cause double-strand breaks (DSBs) of DNA, block the replication machinery, thus trigger cancer cell apoptosis. When injected intravenously into the body, HLX42 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.

PD-L1 is a trans-membrane protein considered to be a co-inhibitory factor of the immune response, it can combine with PD-1 to reduce the proliferation of PD-L1 positive tumour cells, inhibit their cytokine secretion and induce apoptosis.Immune checkpoint inhibitors represented by PD-1/PD-L1 monoclonal antibodies have emerged in recent years and revolutionised all lines of treatment for tumour patients. However, there are still many patients with positive PD-L1 expression who do not respond to or develop resistance to PD-1/PD-L1-targeted therapy. PD-L1 is expressed in patients across a broad spectrum of tumour types including non-small cell lung cancer (NSCLC), colorectal cancer (CRC), triple negative breast cance r(TNBC) and displays limited expression on normal tissues, highlighting the potential of PD-L1 as a target for ADCs in addition to its role as an immune checkpoint, which may bring promising effective treatment option for patients failed to benefit from PD-1/L1 immunotherapy.

Combining the selectivity of targeted mAb with the highly potent cytotoxic agent, HLX42 and HLX43 exhibited good anti-tumour effects and favourable safety profiles in non-clinical pharmacological studies, pharmacokinetic studies and safety evaluation. Meanwhile, HLX42 has shown potent tumour suppression in several CDX and PDX models that were EGFR TKIs or cetuximab resistant. HLX43 has shown potent tumour suppression in several CDX and PDX models that were PD-1/L1 mAb resistant. What’s more, the results of the preclinical studies of these two ADC candidates were published as poster presentations at the 2023 European Society of Medical Oncology (ESMO) Congress. And the phase 1 clinical trials will be initiated to evaluate the safety, tolerance and pharmacokinetics of the ADC projects in patients with advanced/metastatic solid tumours.

Henlius is a global biopharmaceutical company with the vision to offer high-quality, affordable, and innovative biologic medicines for patients worldwide with a focus on oncology, autoimmune diseases, and ophthalmic diseases.

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