PO.IM01.11 · 免疫学
靶向TIGIT免疫检查点的新型多肽抑制剂的发现与临床前评估
Discovery and preclinical evaluation of novel peptide inhibitors targeting the TIGIT immune checkpoint
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
免疫检查点（IC）受体负性调节免疫反应，在维持自身耐受和预防自身免疫方面发挥关键作用。然而，肿瘤细胞可利用这些通路逃避免疫识别和破坏。TIGIT已成为一种关键的免疫检查点受体，通过直接和间接机制发挥免疫抑制作用。虽然TIGIT阻断性单克隆抗体的临床前研究显示出令人鼓舞的抗肿瘤活性，但抗TIGIT单药治疗的临床试验结果令人失望，使关注转向替代策略。在本研究中，我们鉴定出针对TIGIT的潜在多肽类抑制剂。通过计算亲和力成熟，从抗TIGIT抗体MG1131出发，我们鉴定出一个TIGIT抑制性多肽文库。该过程整合了序列采样、分子动力学和自由能计算，并以蒙特卡洛选择为指导。与传统单克隆抗体相比，这些多肽有望提供更优的组织穿透性、更低的免疫原性和更好的安全性特征。在本研究中，两个突变多肽（命名为T-M2和T-M3）在基于hTIGIT-CHO-K1细胞的阻断实验中表现出比野生型多肽更强的对TIGIT-CD155相互作用的抑制。此外，这些多肽诱导人CD4+和CD8+ T细胞分泌更高水平的IFN-gamma。这种增强的免疫刺激活性在hTIGIT-Jurkat和hCD155-CHO-K1细胞的共培养系统中得到证实，其中突变多肽诱导了更高的IL-2分泌。这些多肽作为单药或与免疫检查点抑制剂联合的体内治疗疗效，目前正在MC38荷瘤和人源化HCT116小鼠模型中进行评估。将在治疗组中评估肿瘤生长动态，以及肿瘤微环境、肿瘤引流淋巴结和脾脏中T细胞的表型、细胞因子谱和活化状态，并与对照组进行比较。总之，本研究引入了新型TIGIT阻断多肽作为癌症免疫治疗的有前景候选物，为基于抗体的免疫检查点阻断提供了一种潜在的替代或补充方法。
查看英文原文 English abstract
Immune checkpoint (IC) receptors negatively regulate immune responses and play crucial roles in maintaining self-tolerance and preventing autoimmunity. However, tumor cells can exploit these pathways to evade immune recognition and destruction. TIGIT has emerged as a key immune checkpoint receptor, which exerts immunosuppressive effects through direct and indirect mechanisms. While preclinical studies with TIGIT-blocking monoclonal antibodies demonstrated encouraging antitumor activity, clinical trials of anti-TIGIT monotherapy showed disappointing outcomes, shifting attention toward alternative strategies. In this study, we identified potential peptide-based inhibitors against TIGIT. Through computational affinity maturation, starting from the anti-TIGIT antibody MG1131, we identified a library of TIGIT-inhibitory peptides. This process integrated sequence sampling, molecular dynamics, and free energy calculations, guided by Monte Carlo selection. Compared with conventional monoclonal antibodies, these peptides are expected to provide superior tissue penetration, reduced immunogenicity, and an improved safety profile. In this study, two mutant peptides (named T-M2 and T-M3) exhibited stronger inhibition of TIGIT-CD155 interactions than the wild-type peptide in hTIGIT-CHO-K1 cell-based blocking assay. Furthermore, these peptides induced higher levels of IFN-gamma secretion from both human CD4+ and CD8+ T cells. This enhanced immunostimulatory activity was confirmed in a co-culture system of hTIGIT-Jurkat and hCD155-CHO-K1 cells, where the mutant peptides induced greater IL-2 secretion. The in vivo therapeutic efficacy of these peptides, either as monotherapy or in combination with immune checkpoint inhibitors, is currently being evaluated in MC38 tumor-bearing and humanized HCT116 mouse models. Tumor growth dynamics, as well as the phenotype, cytokine profile and activation status of T cells in the tumor microgovernment, tumor-draining lymph nodes, and spleens will be assessed in the treated groups and compared with control groups. Collectively, this study introduces novel TIGIT-blocking peptides as promising candidates for cancer immunotherapy, offering a potential alternative or complementary approach to antibody-based immune checkpoint blockade.
利益披露 Disclosure
H. Cui, None..
X. Zhang, None..
W. Wang, None..
F. Zonta, None..
E. Elkord, None.