Development of Peptide Paratope Mimics Derived from the Anti-ROR1 Antibody and Long-Acting Peptide–Drug Conjugates for Targeted Cancer Therapy

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 (IC₅₀ = 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.