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 (KD = 1.72 × 10–9 M), internalization
efficiency, anticancer potency (IC50 = 0.015 ± 0.002
μM), and pharmacokinetics (t1/2 =
2.6 h), showcasing a rational approach for designing PDCs with favorable
tissue distribution and strong tumor penetration.