Improved Tumor Penetration and Single-Cell Targeting of Antibody-Drug Conjugates Increases Anticancer Efficacy and Host Survival.

Abstract

Current antibody-drug conjugates (ADC) have made advances in engineering the antibody, linker, conjugation site, small-molecule payload, and drug-to-antibody ratio (DAR). However, the relationship between heterogeneous intratumoral distribution and efficacy of ADCs is poorly understood. Here, we compared trastuzumab and ado-trastuzumab emtansine (T-DM1) to study the impact of ADC tumor distribution on efficacy. In a mouse xenograft model insensitive to trastuzumab, coadministration of trastuzumab with a fixed dose of T-DM1 at 3:1 and 8:1 ratios dramatically improved ADC tumor penetration and resulted in twice the improvement in median survival compared with T-DM1 alone. In this setting, the effective DAR was lowered, decreasing the amount of payload delivered to each targeted cell but increasing the number of cells that received payload. This result is counterintuitive because trastuzumab acts as an antagonist in vitro and has no single-agent efficacy in vivo, yet improves the effectiveness of T-DM1 in vivo Novel dual-channel fluorescence ratios quantified single-cell ADC uptake and metabolism and confirmed that the in vivo cellular dose of T-DM1 alone exceeded the minimum required for efficacy in this model. In addition, this technique characterized cellular pharmacokinetics with heterogeneous delivery after 1 day, degradation and payload release by 2 days, and in vitro cell killing and in vivo tumor shrinkage 2 to 3 days later. This work demonstrates that the intratumoral distribution of ADC, independent of payload dose or plasma clearance, plays a major role in ADC efficacy.Significance: This study shows how lowering the drug-to-antibody ratio during treatment can improve the intratumoral distribution of a antibody-drug conjugate, with implications for improving the efficacy of this class of cancer drugs. Cancer Res; 78(3); 758-68. ©2017 AACR.

• Authors: Cornelius Cilliers, Bruna Menezes, Ian Nessler, Jennifer Linderman, Greg M Thurber
• Journal: Cancer research (Cancer Res) Vol. 78 Issue 3 Pg. 758-768 (02 01 2018) ISSN: 1538-7445 [Electronic] United States
• PMID: 29217763 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: ©2017 American Association for Cancer Research.

Chemical References

• Antibodies, Monoclonal, Humanized
• Immunoconjugates
• Maytansine
• ERBB2 protein, human
• Receptor, ErbB-2
• Trastuzumab
• Ado-Trastuzumab Emtansine

Topics

• Ado-Trastuzumab Emtansine
• Animals
• Antibodies, Monoclonal, Humanized
• Apoptosis (drug effects)
• Cell Proliferation
• Female
• Humans
• Immunoconjugates (pharmacology)
• Maytansine (analogs & derivatives, pharmacology)
• Mice
• Mice, Nude
• Receptor, ErbB-2 (metabolism)
• Single-Cell Analysis
• Stomach Neoplasms (drug therapy, metabolism, pathology)
• Trastuzumab (pharmacology)
• Tumor Cells, Cultured
• Xenograft Model Antitumor Assays