Nanobody-based CD38-specific heavy chain antibodies induce killing of multiple myeloma and other hematological malignancies.

Abstract

Rationale: CD38 is a target for the therapy of multiple myeloma (MM) with monoclonal antibodies such as daratumumab and isatuximab. Since MM patients exhibit a high rate of relapse, the development of new biologics targeting alternative CD38 epitopes is desirable. The discovery of single-domain antibodies (nanobodies) has opened the way for a new generation of antitumor therapeutics. We report the generation of nanobody-based humanized IgG1 heavy chain antibodies (hcAbs) with a high specificity and affinity that recognize three different and non-overlapping epitopes of CD38 and compare their cytotoxicity against CD38-expressing hematological cancer cells in vitro, ex vivo and in vivo. Methods: We generated three humanized hcAbs (WF211-hcAb, MU1067-hcAb, JK36-hcAb) that recognize three different non-overlapping epitopes (E1, E2, E3) of CD38 by fusion of llama-derived nanobodies to the hinge- and Fc-domains of human IgG1. WF211-hcAb shares the binding epitope E1 with daratumumab. We compared the capacity of these CD38-specific hcAbs and daratumumab to induce CDC and ADCC in CD38-expressing tumor cell lines in vitro and in patient MM cells ex vivo as well as effects on xenograft tumor growth and survival in vivo. Results: CD38-specific heavy chain antibodies (WF211-hcAb, MU1067-hcAb, JK36-hcAb) potently induced antibody-dependent cellular cytotoxicity (ADCC) in CD38-expressing tumor cell lines and in primary patient MM cells, but only little if any complement-dependent cytotoxicity (CDC). In vivo, CD38-specific heavy chain antibodies significantly reduced the growth of systemic lymphomas and prolonged survival of tumor bearing SCID mice. Conclusions: CD38-specific nanobody-based humanized IgG1 heavy chain antibodies mediate cytotoxicity against CD38-expressing hematological cancer cells in vitro, ex vivo and in vivo. These promising results of our study indicate that CD38-specific hcAbs warrant further clinical development as therapeutics for multiple myeloma and other hematological malignancies.

• Authors: Levin Schriewer, Kerstin Schütze, Katharina Petry, Julia Hambach, William Fumey, Julia Koenigsdorf, Natalie Baum, Stephan Menzel, Björn Rissiek, Kristoffer Riecken, Boris Fehse, Jana Larissa Röckendorf, Joanna Schmid, Birte Albrecht, Hans Pinnschmidt, Francis Ayuk, Nicolaus Kröger, Mascha Binder, Gunter Schuch, Timon Hansen, Friedrich Haag, Gerhard Adam, Friedrich Koch-Nolte, Peter Bannas
• Journal: Theranostics (Theranostics) Vol. 10 Issue 6 Pg. 2645-2658 ( 2020) ISSN: 1838-7640 [Electronic] Australia
• PMID: 32194826 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © The author(s).

Chemical References

• Antibodies, Monoclonal, Humanized
• Epitopes
• Immunoglobulin G
• Immunoglobulin Heavy Chains
• Membrane Glycoproteins
• Single-Domain Antibodies
• CD38 protein, human
• ADP-ribosyl Cyclase 1

Topics

• ADP-ribosyl Cyclase 1 (immunology)
• Aged
• Animals
• Antibodies, Monoclonal, Humanized (therapeutic use)
• Cell Line, Tumor
• Epitopes (immunology)
• Female
• Hematologic Neoplasms (drug therapy)
• Humans
• Immunoglobulin G (therapeutic use)
• Immunoglobulin Heavy Chains (therapeutic use)
• Male
• Membrane Glycoproteins (immunology)
• Mice
• Mice, SCID
• Middle Aged
• Multiple Myeloma (drug therapy)
• Single-Domain Antibodies (therapeutic use)