Development of Peptide Paratope Mimics Derived from the Anti-ROR1 Antibody and Long-Acting Peptide–Drug Conjugates for Targeted Cancer Therapy
Yang Zhang, Yiqing Fan, Shuyu Liu, Yonghui Guan, Jiale Wan, Qiang Ren, Jialing Wang, Li Zhong, Zhipeng Hu, Wei Shi, Hai Qian
Abstract
Antibody-based targeted therapy in cancer faces a challenge due to uneven antibody distribution in solid tumors, hindering effective drug delivery. We addressed this by developing peptide mimetics with nanomolar-range affinity for Receptor Tyrosine Kinase-Like Orphan Receptor 1 (ROR1) using computational methods. These peptides showed both specific targeting and deep penetration in vitro and in vivo . Additionally, we created peptide-drug conjugates (PDCs) by linking targeting peptides to toxin drugs via various linkers and enhancing their in vivo half-life with fatty side chains for albumin binding. The antitumor candidate II-3 displayed exceptional affinity ( K D = 1.72 × 10 –9 M), internalization efficiency, anticancer potency (IC 50 = 0.015 ± 0.002 μM), and pharmacokinetics ( t 1/2 = 2.6 h), showcasing a rational approach for designing PDCs with favorable tissue distribution and strong tumor penetration.