PO.IM01.14 · 免疫学
BB-202，一种新型抗PD-1/抗VEGF双特异性抗体的抗肿瘤活性
The anti-tumor activity of BB-202, a novel anti-PD-1/anti-VEGF bispecific antibody
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
背景：靶向PD-1/PD-L1的免疫检查点阻断和VEGF抑制各自调节肿瘤微环境，两者的联合在临床前模型中显示出协同抗肿瘤效应。在临床上，抗PD-1/PD-L1抗体与抗血管生成药物的联合改善了多种癌症的疗效，并促成了若干监管批准。在单个分子内共靶向PD-1和VEGF的双特异性抗体代表了进一步增强这种协同作用的有前景的策略。虽然抗PD-1/抗VEGF双特异性抗体依沃西单抗（ivonescimab，AK112）已显示出临床获益，但我们开发了BB-202，一种具有独特结构、旨在提高效力和稳定性的新型双特异性抗体。
方法：BB-202使用帕博利珠单抗来源的Fab区和抗VEGF VHH片段融合到人IgG1 Fc上进行工程化设计。使用全细胞结合测定表征PD-1结合亲和力。使用基于细胞的报告测定评估PD-1和VEGFA阻断，并在混合淋巴细胞反应（MLR）测定中进一步评估PD-1功能阻断。在多种小鼠异种移植模型（包括PBMC人源化小鼠模型）中检测体内疗效和安全性。
结果：BB-202表现出与帕博利珠单抗相当的高PD-1结合亲和力。在PD-1/PD-L1阻断测定中，BB-202显示出与帕博利珠单抗相似、且显著高于AK112和LM-299的效力。BB-202还阻断VEGFA活性，效力与贝伐珠单抗（Avastin）、AK112和LM-299相当。在MLR测定中，BB-202诱导了强健的人T细胞激活，表现出约为AK112的38倍的效力。该分子还显示出优异的加速稳定性和血清稳定性。在体内，BB-202显示出强大的抗肿瘤活性。在NCI-H1975 PBMC人源化小鼠模型中，BB-202实现了比等摩尔剂量帕博利珠单抗显著更大的肿瘤生长抑制。在NCI-HCC827异种移植模型中观察到一致的结果，BB-202再次优于帕博利珠单抗。未检测到体重减轻或可观察到的毒性。
结论：BB-202是一种强效、稳定且耐受性良好的抗PD-1/抗VEGF双特异性抗体。其优越的体外效力和强健的体内疗效，加上良好的可开发性特征，使BB-202成为PD-1/VEGF靶向双特异性抗体中有前景的同类最佳治疗候选药物。
查看英文原文 English abstract
Background: Immune checkpoint blockade targeting PD-1/PD-L1 and VEGF inhibition each modulates the tumor microenvironment, and their combination has shown synergistic anti-tumor effects in preclinical models. Clinically, combining anti-PD-1/PD-L1 antibodies with anti-angiogenic agents has improved outcomes across multiple cancers and led to several regulatory approvals. Bispecific antibodies that co-target PD-1 and VEGF within a single molecule represent a promising strategy to further enhance this synergy. While the anti-PD-1/anti-VEGF bispecific antibody ivonescimab (AK112) has demonstrated clinical benefit, we developed BB-202, a novel bispecific antibody with a distinct structure designed to improve potency and stability.
Methods: BB-202 was engineered using pembrolizumab-derived Fab regions and anti-VEGF VHH fragments fused to a human IgG1 Fc. PD-1 binding affinity was characterized using whole-cell binding assays. PD-1 and VEGFA blockade were assessed using cell-based reporter assays, and PD-1 functional blockade was further evaluated in mixed lymphocyte reaction (MLR) assays. In vivo efficacy and safety were examined in multiple mouse xenograft models, including PBMC-humanized mouse models.
Results: BB-202 demonstrated high PD-1 binding affinity equivalent to pembrolizumab. In PD-1/PD-L1 blockade assays, BB-202 showed potency similar to pembrolizumab and substantially greater than AK112 and LM-299. BB-202 also blocked VEGFA activity with potency comparable to bevacizumab (Avastin), AK112, and LM-299. In MLR assays, BB-202 induced robust human T-cell activation, exhibiting approximately 38-fold greater potency than AK112. The molecule also showed excellent accelerated and serum stability.In vivo, BB-202 demonstrated strong anti-tumor activity. In an NCI-H1975 PBMC-humanized mouse model, BB-202 achieved significantly greater tumor growth inhibition than an equimolar dose of pembrolizumab. Consistent results were observed in the NCI-HCC827 xenograft model, where BB-202 again outperformed pembrolizumab. No weight loss or observable toxicities were detected.
Conclusion: BB-202 is a potent, stable, and well-tolerated anti-PD-1/anti-VEGF bispecific antibody. Its superior in vitro potency and robust in vivo efficacy, together with a favorable developability profile, position BB-202 as a promising best-in-class therapeutic candidate among PD-1/VEGF-targeting bispecific antibodies.
利益披露 Disclosure
M. Yang, None.