Henlius Announces NMPA Approvals of Two ADC Candidates for IND

SHANGHAI, Oct. 27, 2023 /PRNewswire/ — Shanghai Henlius Biotech, Inc. (2696. HK) 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-Targeting ADC Candidate HLX42

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^[1]. 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^[2]. ADC technology has vastly advanced in the last several years and provide a new treatment option for tumour patients^[3]. 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-Targeting ADC Candidate HLX43

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^[4].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^[5]. 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 cancer(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^[6].

HLX43 is a novel PD-L1-targeting ADC, comprised of a high-affinity humanised IgG1 mAb targeting PD-L1 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, HLX43 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 HLX43 to possess a higher therapeutic index and potency for treatment of solid tumours.

Combining the selectivity of targeted mAb with the highly potent cytotoxic agent, HLX42 and HLX43 exhibited good anti-tumour effects and favorable 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.

Looking forward, Henlius will further take efforts to promote the layout of our innovative portfolio by focusing on antibody and novel conjugating technologies, bringing more high-quality and affordable therapeutics for patients worldwide.

About Henlius

Henlius (2696.HK) 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. Up to date, 5 products have been launched in China, 1 has been approved for marketing in overseas markets, 19 indications are approved worldwide, and 2 marketing applications have been accepted for review in the U.S. and the EU, respectively. Since its inception in 2010, Henlius has built an integrated biopharmaceutical platform with core capabilities of high-efficiency and innovation embedded throughout the whole product life cycle including R&D, manufacturing and commercialization. It has established global innovation centers and Shanghai-based manufacturing facilities in line with global Good Manufacturing Practice (GMP), including Xuhui Plant certificated by China and the EU GMP and Songjiang First Plant certificated by China GMP.

Henlius has pro-actively built a diversified and high-quality product pipeline covering over 20 innovative monoclonal antibodies (mAbs) and has continued to explore immuno-oncology combination therapies with proprietary HANSIZHUANG (anti-PD-1 mAb) as backbone. Apart from the launched products HANLIKANG (rituximab), the first China-developed biosimilar, HANQUYOU (trastuzumab for injection, trade name in Europe: Zercepac^®; trade names in Australia: Tuzucip^® and Trastucip^®), the first China-developed mAb biosimilar approved both in China and Europe, HANDAYUAN (adalimumab) and HANBEITAI (bevacizumab), the innovative product HANSIZHUANG has been approved by the NMPA for the treatment of MSI-H solid tumors, squamous non-small cell lung cancer (sqNSCLC), extensive-stage small cell lung cancer (ES-SCLC) and esophageal squamous cell carcinoma (ESCC), making it the world’s first anti-PD-1 mAb for the first-line treatment of SCLC. What’s more, Henlius has conducted over 30 clinical studies for 16 products, expanding its presence in major markets as well as emerging markets.

References

[1] Ni cholson, Robert Ian, Julia Margaret Wendy Gee, and Maureen Elaine Harper. EGFR and cancer prognosis. European journal of cancer 37 (2001): 9-15.
[2] Tan, Chee Seng, D. Gilligan, and S. Pacey. Treatment approaches for EGFR-inhibitor-resistant patients with non-small-cell lung cancer. The Lancet Oncology 16.9(2015): e447-59.
[3] Ponziani S, Di Vittorio G, Pitari G, et al. Antibody-Drug Conjugates: The New Frontier of Chemotherapy. Int J Mol Sci. 2020 Jul 31;21(15):5510.
[4] Han Y, Liu D, Li L. PD-1/PD-L1 pathway: current researches in cancer[J]. American Journal of Cancer Research, 2020, 10(3):727-742.
[5] Attili I, Tarantino P, Passaro A, et al. Strategies to overcome resistance to immune checkpoint blockade in lung cancer[J]. Lung cancer: Journal of the International Association for the Study of Lung Cancer, 2021(154-):154.
[6] Kwan B, Ramirez M, Jin S, et al. 783 SGN-PDL1V, a novel, investigational PD-L1-directed antibody-drug conjugate for the treatment of solid tumors[J]. 2021. 

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