Glycovariant anti-CD37 monospecific protein therapeutic exhibits enhanced effector cell-mediated cytotoxicity against chronic and acute B cell malignancies.

Abstract

TRU-016 is a SMIP(TM) (monospecific protein therapeutic) molecule against the tetraspanin transmembrane family protein CD37 that is currently in Phase 2 trials in Chronic Lymphocytic Leukemia (CLL) and Non-Hodgkin Lymphoma (NHL). In an attempt to enhance the ADCC function of SMIP-016, the chimeric version of TRU-016, SMIP-016(GV) was engineered with a modification in a glycosylation site in the Fc domain. The wild-type and glycovariant SMIP proteins mediate comparable Type I antibody-like direct cytotoxicity in the presence of anti-human Fc crosslinker and show a similar tyrosine phosphorylation pattern post-treatment. However, NK cells stimulated with the SMIP-016(GV) exhibit enhanced activation and release 3-fold more interferon-γ compared with SMIP-016. SMIP-016(GV) shows enhanced ADCC function against cells expressing CD37 with NK cell effectors derived from both normal and CLL-affected individuals. Enhanced ADCC is observed against CLL cells and is sustained at concentrations of SMIP-016(GV) as low at 5E(-6) µg/mL on cells expressing minimal CD37 antigen. In support of the biological relevance of this, SMIP-016(GV) mediates effective ADCC against primary acute lymphoblastic leukemia (ALL) cells with low surface expression of CD37. Collectively, these data suggest potential use of the novel therapeutic agent SMIP-016(GV) with enhanced effector function for B cell malignancies, including CLL and ALL therapy.

• Authors: Sarwish Rafiq, Anthony Siadak, Jonathan P Butchar, Carolyn Cheney, Gerard Lozanski, Naduparambil K Jacob, Rosa Lapalombella, Jackie McGourty, Meghan Moledor, Richard Lowe, Ben Setter, Jeffrey Jones, Joseph M Flynn, Leslie Andritsos, Steven Devine, Xiaokui Mo, David Jarjoura, Susheela Tridandapani, Paul Algate, John C Byrd, Natarajan Muthusamy
• Journal: mAbs (MAbs) 2013 Sep-Oct Vol. 5 Issue 5 Pg. 723-35 ISSN: 1942-0870 [Electronic] United States
• PMID: 23883821 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies, Monoclonal
• Antigens, Neoplasm
• CD37 protein, human
• Immunoglobulin G
• Recombinant Fusion Proteins
• TRU 016
• Tetraspanins

Topics

• Animals
• Antibodies, Monoclonal (genetics, immunology, pharmacology)
• Antibody-Dependent Cell Cytotoxicity (drug effects, immunology)
• Antigens, Neoplasm (immunology)
• Binding Sites (genetics, immunology)
• CHO Cells
• Cell Line, Tumor
• Cell Survival (drug effects, immunology)
• Cricetinae
• Cricetulus
• Dose-Response Relationship, Drug
• Glycosylation
• Humans
• Immunoglobulin G (immunology, pharmacology)
• Killer Cells, Natural (drug effects, immunology)
• Leukemia, Lymphocytic, Chronic, B-Cell (drug therapy, immunology, pathology)
• Macrophages (drug effects, immunology)
• Phagocytosis (drug effects, immunology)
• Precursor B-Cell Lymphoblastic Leukemia-Lymphoma (drug therapy, immunology, pathology)
• Protein Engineering (methods)
• Recombinant Fusion Proteins (immunology, pharmacology)
• Tetraspanins (immunology)
• Tumor Cells, Cultured