KBD880 is a potent and selective GPC3 peptide binder for treatment of HCC

Background: The membrane-associated glycoprotein Glypican-3 (GPC3) is highly overexpressed in hepatocellular carcinoma (HCC) while exhibiting minimal to no expression in normal tissues. This tumor-specific expression profile makes GPC3 an ideal target for developing radiopharmaceutical therapies to treat HCC, a leading cause of cancer-related deaths worldwide. Methods: DOTA-KBD-GPC3 (KBD880) is a radiopharmaceutical conjugate composed of a novel GPC3-binding macrocyclic peptide, a linker, and a DOTA chelator for complexation with therapeutic radioisotopes. The binding affinity of the 175 Lu-labeled conjugate was characterized by surface plasmon resonance and competitive flow cytometry. Subsequently, Target-mediated cellular internalization kinetics were quantified via radiometric assays. In vivo, the biodistribution and therapeutic efficacy of the 177 Lu-labeled conjugate were evaluated in HepG2 HCC xenograft model. Results: 175 Lu-KBD880 exhibited high-affinity binding to both human and murine GPC3, with equilibrium dissociation constants (KD) of 2.20 nM and 2.02 nM, respectively, as determined by surface plasmon resonance. In addition, 175 Lu-KBD880 showed potent binding to GPC3-expressing HepG2 cells (IC 50 = 9.3 nM). A high proportion of non-canonical amino acids and fragments with favorable drug-like properties were used to achieve a balance of potency, permeability, and physicochemical properties. 175 Lu-KBD880 exhibited excellent permeability, an optimal half-life and substantial systemic exposure in mice. The therapeutic conjugate, 177 Lu-KBD880, exhibited rapid and efficient internalization, achieving cellular uptake ratios of 50-60%. 177 Lu-KBD880 displayed an excellent in vivo profile, characterized by high tumor retention, rapid renal clearance, and minimal off-target uptake. This favorable biodistribution translated into significant and sustained tumor growth inhibition following monotherapy in GPC3-positive HCC xenografts. Conclusions: KBD880 is a potent and selective, peptide-based radiopharmaceutical agent developed for targeting GPC3-expressing tumors. Its favorable preclinical characteristics-including an optimal pharmacokinetic profile, targeted biodistribution, and durable monotherapy efficacy-strongly support its development as a theranostic agent for patients with GPC3-positive malignancies.