Mouse CD38-Specific Heavy Chain Antibodies Inhibit CD38 GDPR-Cyclase Activity and Mediate Cytotoxicity Against Tumor Cells
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Mouse CD38-Specific Heavy Chain Antibodies Inhibit CD38 GDPR-Cyclase Activity and Mediate Cytotoxicity Against Tumor Cells. / Baum, Natalie; Eggers, Marie; Koenigsdorf, Julia; Menzel, Stephan; Hambach, Julia; Staehler, Tobias; Fliegert, Ralf; Kulow, Frederike; Adam, Gerhard; Haag, Friedrich; Bannas, Peter; Koch-Nolte, Friedrich.
In: FRONT IMMUNOL, Vol. 12, 703574, 2021.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Mouse CD38-Specific Heavy Chain Antibodies Inhibit CD38 GDPR-Cyclase Activity and Mediate Cytotoxicity Against Tumor Cells
AU - Baum, Natalie
AU - Eggers, Marie
AU - Koenigsdorf, Julia
AU - Menzel, Stephan
AU - Hambach, Julia
AU - Staehler, Tobias
AU - Fliegert, Ralf
AU - Kulow, Frederike
AU - Adam, Gerhard
AU - Haag, Friedrich
AU - Bannas, Peter
AU - Koch-Nolte, Friedrich
N1 - Copyright © 2021 Baum, Eggers, Koenigsdorf, Menzel, Hambach, Staehler, Fliegert, Kulow, Adam, Haag, Bannas and Koch-Nolte.
PY - 2021
Y1 - 2021
N2 - CD38 is the major NAD+-hydrolyzing ecto-enzyme in most mammals. As a type II transmembrane protein, CD38 is also a promising target for the immunotherapy of multiple myeloma (MM). Nanobodies are single immunoglobulin variable domains from heavy chain antibodies that naturally occur in camelids. Using phage display technology, we isolated 13 mouse CD38-specific nanobodies from immunized llamas and produced these as recombinant chimeric mouse IgG2a heavy chain antibodies (hcAbs). Sequence analysis assigned these hcAbs to five distinct families that bind to three non-overlapping epitopes of CD38. Members of families 4 and 5 inhibit the GDPR-cyclase activity of CD38. Members of families 2, 4 and 5 effectively induce complement-dependent cytotoxicity against CD38-expressing tumor cell lines, while all families effectively induce antibody dependent cellular cytotoxicity. Our hcAbs present unique tools to assess cytotoxicity mechanisms of CD38-specific hcAbs in vivo against tumor cells and potential off-target effects on normal cells expressing CD38 in syngeneic mouse tumor models, i.e. in a fully immunocompetent background.
AB - CD38 is the major NAD+-hydrolyzing ecto-enzyme in most mammals. As a type II transmembrane protein, CD38 is also a promising target for the immunotherapy of multiple myeloma (MM). Nanobodies are single immunoglobulin variable domains from heavy chain antibodies that naturally occur in camelids. Using phage display technology, we isolated 13 mouse CD38-specific nanobodies from immunized llamas and produced these as recombinant chimeric mouse IgG2a heavy chain antibodies (hcAbs). Sequence analysis assigned these hcAbs to five distinct families that bind to three non-overlapping epitopes of CD38. Members of families 4 and 5 inhibit the GDPR-cyclase activity of CD38. Members of families 2, 4 and 5 effectively induce complement-dependent cytotoxicity against CD38-expressing tumor cell lines, while all families effectively induce antibody dependent cellular cytotoxicity. Our hcAbs present unique tools to assess cytotoxicity mechanisms of CD38-specific hcAbs in vivo against tumor cells and potential off-target effects on normal cells expressing CD38 in syngeneic mouse tumor models, i.e. in a fully immunocompetent background.
KW - ADP-ribosyl Cyclase 1/genetics
KW - Animals
KW - Antibodies, Monoclonal, Murine-Derived/genetics
KW - Antibodies, Neoplasm/genetics
KW - Antibody-Dependent Cell Cytotoxicity
KW - Cell Line, Tumor
KW - Humans
KW - Immunoglobulin Heavy Chains/genetics
KW - Membrane Glycoproteins/genetics
KW - Mice
KW - Mice, Inbred BALB C
KW - Mice, Knockout
KW - Neoplasms/immunology
U2 - 10.3389/fimmu.2021.703574
DO - 10.3389/fimmu.2021.703574
M3 - SCORING: Journal article
C2 - 34539634
VL - 12
JO - FRONT IMMUNOL
JF - FRONT IMMUNOL
SN - 1664-3224
M1 - 703574
ER -
