Co-administered antibody improves penetration of antibody–dye conjugate into human cancers with implications for antibody–drug conjugates

• Published in: Nature communications Vol. 11; no. 1; pp. 5667 - 11
• Main Authors: Lu, Guolan, Nishio, Naoki, van den Berg, Nynke S., Martin, Brock A., Fakurnejad, Shayan, van Keulen, Stan, Colevas, Alexander D., Thurber, Greg M., Rosenthal, Eben L.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 09.11.2020; Nature Publishing Group; Nature Portfolio
• Subjects: 13/1; 13/51; 14/34; 14/63; 631/154/152; 631/67/1536; 631/67/2321; 692/308/2779/109/1940; Adult; Aged; Aged, 80 and over; Antibodies; Antibodies - administration & dosage; Antibodies - therapeutic use; Cell Line, Tumor; Conjugates; Dosage; Drug Delivery Systems; Drug dosages; Dyes; Female; Fluid penetrant testing; Head and Neck Neoplasms - drug therapy; Head and Neck Neoplasms - pathology; Humanities and Social Sciences; Humans; Immunoconjugates - administration & dosage; Immunoconjugates - therapeutic use; Indoles - administration & dosage; Male; Middle Aged; Monoclonal antibodies; multidisciplinary; Non-Randomized Controlled Trials as Topic; Panitumumab - administration & dosage; Penetration; Prospective Studies; Retrospective Studies; Science; Science (multidisciplinary); Solid tumors; Tissues; Toxicity; Tumors
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-020-19498-y

Poor tissue penetration remains a major challenge for antibody-based therapeutics of solid tumors, but proper dosing can improve the tissue penetration and thus therapeutic efficacy of these biologics. Due to dose-limiting toxicity of the small molecule payload, antibody-drug conjugates (ADCs) are administered at a much lower dose than their parent antibodies, which further reduces tissue penetration. We conducted an early-phase clinical trial (NCT02415881) and previously reported the safety of an antibody-dye conjugate (panitumumab-IRDye800CW) as primary outcome. Here, we report a retrospective exploratory analysis of the trial to evaluate whether co-administration of an unconjugated antibody could improve the intratumoral distribution of the antibody-dye conjugate in patients. By measuring the multiscale distribution of the antibody-dye conjugate, this study demonstrates improved microscopic antibody distribution without increasing uptake (toxicity) in healthy tissue when co-administered with the parent antibody, supporting further clinical investigation of the co-administration dosing strategy to improve the tumor penetration of ADCs. Antibody-drug conjugates targeting high expression receptors can suffer from poor tumour penetration. Here, the authors use unconjugated antibody to improve the penetration of an antibody-dye conjugate in a clinical study, supporting further clinical investigation of the co-administration strategy.