Shanghai Henlius Biotech, Inc. (2696.HK) recently announced that its innovative PD-L1 antibody-drug conjugate (ADC), HLX43, has successfully completed the first patient dosing in a Phase 2 clinical trial. HLX43, which entered Phase 1 clinical trials in November 2023 and is the second PD-L1 ADC globally to progress to clinical research, marks a significant milestone in the development of next-generation cancer therapies.
HLX43 is a cutting-edge PD-L1 ADC co-developed by Henlius and MediLink Therapeutics, utilizing MediLink’s proprietary TMALIN® technology platform for its linker-payload. The molecule’s highly differentiated design has demonstrated a robust bystander effect and superior anti-tumor activity in preclinical studies. Notably, HLX43 has shown no immunotoxicity against PD-L1-positive human antigen-presenting cells, ensuring a favorable safety profile. In hepatocellular carcinoma (HCC) models, HLX43 has exhibited synergistic anti-tumor activity when combined with anti-VEGF antibodies, highlighting its potential for combination therapies.
Pfizer’s PD-L1 ADC, SGN-PDL1V, is currently leading the field, with plans to initiate a pivotal Phase 3 clinical trial for first-line treatment of head and neck squamous cell carcinoma (HNSCC) and second-line or later treatment of non-small cell lung cancer (NSCLC). This trial represents the final proof-of-concept (POC) stage for PD-L1 ADCs.
According to Pfizer’s September 2024 disclosure, SGN-PDL1V demonstrated an objective response rate (ORR) of 27.3% in 55 patients, with a confirmed response rate of 12.7% and a median duration of response (mDoR) of 7.9 months. However, safety concerns remain, with 30.9% of patients experiencing Grade 3 or higher adverse events and 14.5% discontinuing treatment due to side effects.
Currently, only three PD-L1 ADCs have entered clinical development globally, positioning HLX43 as a strong contender in this emerging field. Henlius is actively advancing a series of Phase 2 POC clinical trials for HLX43, targeting a wide range of tumor types, including NSCLC, cervical cancer, hepatocellular carcinoma, and esophageal cancer. The company has also initiated a Phase 1b/2 clinical trial to explore combination therapies involving HLX43 and anti-PD-1 monoclonal antibodies.
Antibody-drug conjugates (ADCs) are increasingly recognized as a targeted alternative to conventional chemotherapy, offering a promising modality for cancer treatment. Recent breakthroughs in combining ADCs with anti-PD-(L)1 antibodies have further expanded their therapeutic potential. PD-L1, which functions both as an immune checkpoint inhibitor and a tumor-associated antigen (TAA), provides a unique dual mechanism of action for PD-L1 ADCs: targeted toxin delivery and immune suppression reversal. This dual mechanism enables PD-L1 ADCs to address a broad spectrum of tumor types.
Initial clinical investigations of HLX43 have thus far yielded encouraging results, with no immunotoxicity observed against PD-L1-positive human antigen-presenting cells. This aligns with predefined safety objectives while demonstrating favorable efficacy. Building on these compelling Phase 1 results, HLX43 has rapidly progressed to Phase 2 trials, with further clinical achievements anticipated.
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