2025 AACR | 复宏汉霖多项创新管线临床前研究数据首次发布

摘要标题：一款兼具免疫检查点抑制、抗血管生成及抗肿瘤活性的新型抗PD-L1/VEGF双特异性抗体HLX37

A novel anti-PD-L1/VEGF bispecific antibody (HLX37) with immune checkpoint inhibition, anti-angiogenic, and antineoplastic activities

分会场标题：Overcoming Checkpoint Inhibition and Tumor Suppression

展示形式：摘要及壁报  

摘要编号：7303

展示时间：美国中部时间4月30日（周三）9:00 AM-12:00 PM

展示地点：第39区，展板#18

靶向PD-L1与VEGF的双特异性抗体通过结合肿瘤细胞表面的PD-L1，增强抗VEGF药物向肿瘤部位的递送，从而在肿瘤微环境（TME）中实现血管正常化与T细胞激活的协同效应，最终提升抗肿瘤活性。

HLX37是一款经合理设计的PD-L1/VEGF双特异性抗体。体外研究显示，HLX37对PD-L1和VEGF均具有较高的亲和力，在VEGF存在时可显著促进PD-L1内吞和下调，同时阻断PD-1/PD-L1和VEGF/VEGFR2信号通路，从而促进T细胞激活并抑制肿瘤血管新生。体内研究表明，HLX37在MDA-MB-231（三阴乳腺癌）、NCI-H292（肺癌）等肿瘤模型中呈现剂量依赖的抗肿瘤疗效。与抗VEGF单抗和抗PD-L1单抗的联合用药组相比，HLX37显示出更高的肿瘤富集效应，该效应可能由PD-L1和VEGF共同介导。在食蟹猴毒性实验中，HLX37在100 mg/kg的给药剂量，单周静脉输注3次的频率下表现出良好的耐受性。鉴于HLX37具有优异的临床前抗肿瘤活性且安全性可控，且能增强肿瘤富集效应，其在多类肿瘤中具有广泛的应用潜力。

摘要标题：一款具有显著抗肿瘤活性及低血液毒性的新型KAT6A/B抑制剂的发现

Identification of novel KAT6A/B inhibitors with enhanced antitumor activity and reduced hematologic toxicity

分会场标题：Lead Identification and Optimization

展示形式：摘要及壁报  

摘要编号：6976

展示时间：美国中部时间4月30日（周三）9:00 AM-12:00 PM

展示地点：第25区，展板#5

HLX97是潜在的同类最佳的KAT6A/B抑制剂。KAT6A/B是乳腺癌治疗中极具潜力的靶点。一项针对KAT6A/B抑制剂PF-07248144的I期临床研究显示出积极的疗效，但其靶点相关的血液学毒性（尤其是中性粒细胞减少症）可能限制药物剂量的递增。复宏汉霖致力于开发一款具有“快速起效/快速清除”药代动力学特性的高选择性KAT6A/B抑制剂，旨在最大化药物抗肿瘤活性的同时减轻产品的血液毒性。

与参比化合物PF-07248144相比，HLX97展现出更强的KAT6A/B抑制活性和对KAT5/7/8更高的选择性，并在ZR-75-1细胞模型中产生更强的细胞毒效应。同时，HLX97显示出良好的ADME特性，包括高口服生物利用度和优异的药代动力学特征。在ZR-75-1异种移植模型中，经过五周治疗，HLX97显示出剂量依赖的体内抗肿瘤疗效，且动物体重下降极小。我们认为，HLX97更强的KAT6A/B抑制能力和"相对更快的"体内清除速率可能共同促成了其更宽的治疗窗口。在大鼠单次给药急性毒性试验中，HLX97在100 mg/kg剂量下耐受良好。基于HLX97优异的疗效和安全性特征，复宏汉霖计划于2025年底递交该产品的新药临床试验（IND）申请。

摘要标题：一款通过持续激活未折叠蛋白反应（UPR）实现独特杀伤机制的新型抗体偶联药物（ADC）连接子-载荷组合的发现

Discovery of a novel antibody-drug conjugate linker-payload with a distinct killing mechanism via prolonged unfolded protein response activation

分会场标题：Drug Design, Synthesis, and Disposition

展示形式：摘要及壁报  

摘要编号：5730

展示时间：美国中部时间4月29日（周二）2:00 PM-5:00 PM

展示地点：第25区，展板#1

一类具有3-(4-羟苯基吲哚啉-2骨架结构的化合物，通过持续激活未折叠蛋白反应（UPR），对高表达TRPM4或雌激素受体阳性的癌细胞展现出强效抗肿瘤活性，该杀伤机制与现有毒素不同。此类化合物对多数健康组织毒性较低，主要副作用为胃肠道毒性，代表性化合物包括ErSO和泻药醋酸氧苯乙酯。为克服ADC耐药性，或与现有ADC产生协同，复宏汉霖构建了一类全球首创的ADC 连接子-荷载毒素—我们以此类化合物优化后得到的HLX91-048作为毒素载荷，通过可裂解的GGFG连接子与抗HER2抗体偶联，形成药物抗体比（DAR）为4或8的偶联物。

研究表明，与ErSO相比，HLX91-048的细胞毒性提升了10倍以上，在多类肿瘤细胞中显示出亚纳摩尔至纳摩尔级别的IC50值。相较于DS-8201类似物，基于HLX91-048的抗体药物偶联物（ADC）在多种细胞系中表现出更强的细胞毒性、更显著的旁观者杀伤效应，并且在人及猴血浆中稳定性更高。研究证实，基于HLX91-048的ADC可显著激活未折叠蛋白反应（UPR），与预期一致。基于HLX91-048的DAR4（药物抗体比4）的HER2 ADC在BT474和NCI-N87模型中均显示出剂量依赖性的抗肿瘤效果，在较高剂量（10-12 mg/kg）下实现显著的肿瘤消退。值得注意的是，基于HLX91-048的ADC在部分对DS-8201类似物无应答的耐药患者来源的类器官（PDO）模型中仍保持敏感性。在大鼠临床前毒理学评估中，DS-8201类似物和基于HLX91-048的ADC在60 mg/kg剂量下（每周一次，持续三周）均表现出良好的耐受性。基于HLX91-048的连接子-载荷组合具有高度差异化的作用机制，并在临床前评估中展现出卓越的疗效与安全性。其针对非人灵长类动物的初步毒理学研究已纳入开发计划。

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.

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.

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.

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