Shanghai, China, April 28, 2025 – Shanghai Henlius Biotech, Inc. (2696. HK) announced that three latest preclinical research results from its pipeline programs will be published in poster presentations at the American Association for Cancer Research 2025 Annual Meeting (AACR 2025), covering a novel anti-PD-L1/VEGF bispecific antibody HLX37, a novel KAT6A/B inhibitor with best-in-class potential, and a first-in-class ADC linker-payload featuring a highly differentiated killing mechanism.
The detailed data of the studies released at AACR 2025 are as follows:
HLX37 (anti-PD-L1/VEGF BsAb)
Title: A novel anti-PD-L1/VEGF bispecific antibody (HLX37) with immune checkpoint inhibition, anti-angiogenic, and antineoplastic activities
Session Title: Overcoming Checkpoint Inhibition and Tumor Suppression
Form: Abstract and poster
Abstract Number: 7303
Date and Time: April 30, 2025, 9:00 AM-12:00 PM CST
Location: Poster Section 39, Board #18
The bispecific antibody targeting PD-L1 and VEGF enhances anti-VEGF delivery to the tumor site by binding to tumor PD-L1, promoting synergistic effects of blood vessel normalization and T cell activation within the tumor microenvironment, thus improving anti-tumor activity.
HLX37 is a rationally designed PD-L1/VEGF bispecific antibody. In vitro assays demonstrated that HLX37 exhibits high binding affinity for both PD-L1 and VEGF. In the presence of VEGF, HLX37 dramatically promoted cell surface PD-L1 binding and internalization, showing dual blockade activity against PD-1/PD-L1 and VEGF/VEGFR2, thereby reversing T cell exhaustion and inhibiting tumor angiogenesis. It conferred robust tumor inhibition activity and dose-dependent tumor suppression in the MDA-MB231 and NCI-H292 models. Compared to the combination group of anti-PD-1 monoclonal antibody and anti-VEGF monoclonal antibody, the anti-PD-L1/VEGF bispecific antibody showed enhanced tumor enrichment. The distribution of anti-PD-L1/VEGF is mediated by both PD-L1 and VEGF, HLX37 was well tolerated in cynomolgus monkeys after three weekly intravenous doses of 100 mg/kg. These data suggested that HLX37 has strong preclinical efficacy and favorable safety profile, with enhanced tumor enrichment. HLX37 holds promising potential for further application in various types of cancer.
HLX97 (KAT6A/B inhibitor)
Title: Identification of novel KAT6A/B inhibitors with enhanced antitumor activity and reduced hematologic toxicity
Session Title: Lead Identification and Optimization
Form: Abstract and poster
Abstract Number: 6976
Date and Time: April 30, 2025, 9:00 AM-12:00 PM CST
Location: Poster Section 25, Board #5
HLX97 is a novel KAT6A/B inhibitor with best-in-class potential. KAT6A/B are promising targets for breast cancer therapy. A phase 1 study of the KAT6A/B inhibitor PF-07248144 showed encouraging clinical results; however, target-associated hematologic toxicity, particularly neutropenia, may hinder dose escalation. Henlius aims to identify potent and highly selective KAT6A/B inhibitors with "fast-on, fast-off" pharmacokinetic profiles in vivo, enabling sustained antitumor efficacy while minimizing hematologic toxicity.
HLX97 exhibited superior enzymatic inhibition and enhanced selectivity against KAT5/7/8, along with more potent cytotoxic effects in ZR-75-1 cells, in head-to-head comparisons with PF-07248144. Meanwhile, HLX97 displayed favorable ADME characteristics, such as high oral bioavailability and excellent pharmacokinetics. In a ZR-75-1 xenograft model, HLX97 demonstrated dose-dependent antitumor efficacy with minimal weight loss over a five-week treatment period. We propose that the more robust KAT6A/B inhibition and “relatively faster” clearance of HLX97 may contribute to its broader therapeutic window. The compounds were well tolerated at 100 mg/kg in a single-dose acute toxicity study in rats. HLX97 represents a best-in-class KAT6A/B inhibitor with optimized efficacy and safety profiles. An Investigational New Drug (IND) application is anticipated to be submitted by the end of 2025.
Novel ADC Linker-payload
Title: Discovery of a novel antibody-drug conjugate linker-payload with a distinct killing mechanism via prolonged unfolded protein response activation
Session Title: Drug Design, Synthesis, and Disposition
Form: Abstract and poster
Abstract Number: 5730
Date and Time: April 29, 2025, 2:00 PM-5:00 PM CST
Location: Poster Section 25, Board #1
A specific class of compounds featuring a 3-(4-hydroxyphenyl) indoline-2 scaffold demonstrated potent antitumor activity against cancer cells with elevated TRPM4 expression or estrogen receptor positivity through the sustained activation of unfolded protein response. This mechanism is distinct from existing toxins. Generally, these compounds exhibit low toxicity to most healthy tissues, with gastrointestinal toxicity being the primary adverse effect. Notable examples of this class include ErSO and laxative oxyphenisatin acetate. To overcome ADC resistance or synergize with existing ADCs, Henlius dedicated to develop a first-in-class ADC payload—HLX91-048. To create the HER2-targeting ADC, HLX91-048 was linked to a HER2 antibody via a cleavable GGFG linker, resulting in drug-to-antibody ratio (DAR) of 4 or 8 as needed.
HLX91-048 demonstrates >10-fold increase in cytotoxicity compared to ErSO, exhibiting sub-nanomolar to nanomolar IC50 values across various tumor cell types. When compared to DS-8201 analog the HLX91-048-based ADC showed enhanced cytotoxicity in multiple cell lines, stronger bystander killing, and greater stability in human and monkey plasma. As expected, the HLX91-048-based ADC significantly activates the unfolded protein response (UPR). The DAR4 HER2 ADC derived from HLX91-048 exhibited dose-dependent antitumor efficacy in both BT474 and NCI-N87 models, leading to substantial tumor regression at higher doses (10-12 mpk). Notably, 5 out of 8 PDOs from patients resistant to various standard treatments remained sensitive to the HLX91-048-based ADC, while showing reduced sensitivity to DS-8201. Lastly, in a pre-toxicology evaluation in rats, both the DS-8201 analog and the HLX91-048-based ADC were well-tolerated at a dose of 60 mpk once weekly for three weeks. The HLX91-048 based linker-payload represents a first-in-class ADC platform featuring a highly differentiated killing mechanism that demonstrated exceptional efficacy and safety in preclinical evaluations. Preliminary toxicology studies in non-human primates have been scheduled.