Many advances in antitumor therapies have been achieved with antagonistic antibodies targeting the programmed cell death protein 1 (PD-1) or its ligand (PD-L1); however, many cancer patients still develop resistance to anti–PD-1/PD-L1 treatments often associated with the upregulation of other immune checkpoints such as Lymphocyte Activation Gene-3 (LAG-3). In order to verify whether it is possible to overcome these limits, we analyzed and compared the effects of combinations of the clinically validated anti-LAG-3 mAb (Relatlimab) with anti-PD-1 (Pembrolizumab) or anti-PD-L1 (Atezolizumab) monoclonal antibodies (mAbs) with those of novel bispecific tribodies (TRs), called TR0304 and TR0506, previously generated in our lab by combining the binding moieties of novel human antibodies targeting the same ICs of the mentioned mAbs. In particular, TR0304, made up of a Fab derived from an anti-PD-L1 mAb and two single-chain variable fragments (scFvs) derived from an anti-LAG-3 mAb, was tested in comparison with Relatlimab plus Atezolizumab, and TR0506, made up of an antigen-binding fragment (Fab) derived from the same anti-LAG-3 mAb and two scFvs derived from an anti-PD-1 mAb, was tested in comparison with Relatlimab and Pembrolizumab. We found that the two novel TRs showed similar binding affinity to the targets with respect to validated mAbs, even though they recognized distinct or only partially overlapping epitopes. When tested for their functional properties, they showed an increased ability to induce lymphocyte activation and stronger in vitro cytotoxicity against tumor cells compared to combinatorial treatments of clinically validated mAbs. Considering that tribodies also have other advantages with respect to combinatorial treatments, such as reduced production costs and lower dose requirements, we think that these novel immunomodulatory TRs could be used for therapeutic applications, particularly in monotherapy-resistant cancer patients.
靶向程序性细胞死亡蛋白1（PD-1）或其配体（PD-L1）的拮抗性抗体已在抗肿瘤治疗领域取得诸多进展，但许多癌症患者仍会对抗PD-1/PD-L1治疗产生耐药性，这种耐药常伴随淋巴细胞活化基因-3（LAG-3）等其他免疫检查点的上调。为验证能否突破这些局限，我们分析比较了临床验证的抗LAG-3单克隆抗体（Relatlimab）分别与抗PD-1（Pembrolizumab）或抗PD-L1（Atezolizumab）单抗联用方案的效果，并与本实验室前期构建的新型双特异性三功能抗体TR0304和TR0506进行对比。这两种三功能抗体是通过整合靶向相同免疫检查点的新型人源抗体结合域构建而成。具体而言，由抗PD-L1单抗衍生的抗原结合片段（Fab）与两个源自抗LAG-3单抗的单链可变片段（scFv）组成的TR0304，与Relatlimab联合Atezolizumab方案进行比较；而由相同抗LAG-3单抗衍生的Fab与两个源自抗PD-1单抗的scFv组成的TR0506，则与Relatlimab联合Pembrolizumab方案进行对比。研究发现，尽管这两种新型三功能抗体识别与已验证单抗不同或仅部分重叠的表位，但它们对靶标表现出相似的结合亲和力。在功能特性测试中，相较于临床验证单抗的联合治疗方案，三功能抗体显示出更强的淋巴细胞活化能力及更显著的体外肿瘤细胞杀伤作用。考虑到三功能抗体在降低生产成本和减少剂量需求等方面相较于联合治疗方案具有优势，我们认为这些新型免疫调节性三功能抗体具有治疗应用潜力，尤其适用于单药治疗耐药的癌症患者。
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