Conditional activation of an anti-IgM antibody-drug conjugate for precise B cell lymphoma targeting

Front Immunol. 2023 Sep 28:14:1258700. doi: 10.3389/fimmu.2023.1258700. eCollection 2023.

Abstract

Cancerous B cells are almost indistinguishable from their non-malignant counterparts regarding their surface antigen expression. Accordingly, the challenge to be faced consists in elimination of the malignant B cell population while maintaining a functional adaptive immune system. Here, we present an IgM-specific antibody-drug conjugate masked by fusion of the epitope-bearing IgM constant domain. Antibody masking impaired interaction with soluble pentameric as well as cell surface-expressed IgM molecules rendering the antibody cytotoxically inactive. Binding capacity of the anti-IgM antibody drug conjugate was restored upon conditional protease-mediated demasking which consequently enabled target-dependent antibody internalization and subsequent induction of apoptosis in malignant B cells. This easily adaptable approach potentially provides a novel mechanism of clonal B cell lymphoma eradication to the arsenal available for non-Hodgkin's lymphoma treatment.

Keywords: B cell lymphoma; B cell receptor; MMP-9; antibody-drug conjugate; conditional activated antibody; masked antibody; matriptase.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Humans
  • Immunoconjugates* / pharmacology
  • Immunoconjugates* / therapeutic use
  • Immunoglobulin M
  • Lymphoma, B-Cell* / drug therapy
  • Lymphoma, Non-Hodgkin*

Substances

  • anti-IgM
  • Immunoconjugates
  • Immunoglobulin M

Grants and funding

The authors declare financial support was received for the research, authorship, and/or publication of this article. Funding for this work was provided in part by the Ministry of Higher Education, Research and Arts of the State of Hesse under the LOEWE project "TRABITA".