The Antitumor Activity of IMGN529, a CD37-Targeting Antibody-Drug Conjugate, Is Potentiated by Rituximab in Non-Hodgkin Lymphoma Models.

Abstract

Naratuximab emtansine (IMGN529) is an investigational antibody-drug conjugate consisting of a CD37-targeting antibody conjugated to the maytansine-derived microtuble disruptor, DM1. IMGN529 has shown promising preclinical and clinical activity in non-Hodgkin lymphoma, including diffuse large B-cell lymphoma (DLBCL). Due to the aggressive nature of the disease, DLBCL is often treated with combination therapies to maximize clinical outcomes; therefore, we investigated the potential of combining IMGN529 with both standard-of-care and emerging therapies against multiple oncology-relevant targets and pathways. The strongest enhancement in potency was seen with anti-CD20 antibodies, including rituximab. The combination of IMGN529 and rituximab was more potent than either agent alone, and this combinatorial benefit was associated with increased apoptotic induction and cell death. Additional studies revealed that rituximab treatment increased the internalization and degradation of the CD37-targeting antibody moiety of IMGN529. The combination of IMGN529 and rituximab was highly efficacious in multiple xenograft models, with superior antitumor efficacy seen compared to either agent alone or treatment with R-CHOP therapy. These findings suggest a novel mechanism whereby the potency of IMGN529 can be enhanced by CD20 binding, which results in the increased internalization and degradation of IMGN529 leading to the generation of greater amounts of cytotoxic catabolite. Overall, these data provide a biological rationale for the enhanced activity of IMGN529 in combination with rituximab and support the ongoing clinical evaluation of IMGN529 in combination with rituximab in patients with relapsed and/or refractory DLBCL.

• Authors: Stuart W Hicks, Katharine C Lai, L Cristina Gavrilescu, Yong Yi, Surina Sikka, Prerak Shah, Meghan E Kelly, Jenny Lee, Leanne Lanieri, Jose F Ponte, Callum M Sloss, Angela Romanelli
• Journal: Neoplasia (New York, N.Y.) (Neoplasia) Vol. 19 Issue 9 Pg. 661-671 (Sep 2017) ISSN: 1476-5586 [Electronic] United States
• PMID: 28753442 (Publication Type: Journal Article)
• Copyright: Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Chemical References

• Antibodies, Monoclonal, Humanized
• Rituximab
• naratuximab emtansine

Topics

• Animals
• Antibodies, Monoclonal, Humanized (pharmacology)
• Antibody-Dependent Cell Cytotoxicity (drug effects, immunology)
• Cell Line, Tumor
• Disease Models, Animal
• Drug Synergism
• Female
• Humans
• Lymphoma, Non-Hodgkin (drug therapy, immunology, metabolism, pathology)
• Mice
• Molecular Targeted Therapy
• Proteolysis
• Rituximab (pharmacology)
• Xenograft Model Antitumor Assays