Nanobody-based CD38-specific heavy chain antibodies induce killing of multiple myeloma and other hematological malignancies
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Nanobody-based CD38-specific heavy chain antibodies induce killing of multiple myeloma and other hematological malignancies. / Schriewer, Levin; Schütze, Kerstin; Petry, Katharina; Hambach, Julia; Fumey, William; Koenigsdorf, Julia; Baum, Natalie; Menzel, Stephan; Rissiek, Björn; Riecken, Kristoffer; Fehse, Boris; Röckendorf, Jana Larissa; Schmid, Joanna; Albrecht, Birte; Pinnschmidt, Hans; Ayuk, Francis; Kröger, Nicolaus; Binder, Mascha; Schuch, Gunter; Hansen, Timon; Haag, Friedrich; Adam, Gerhard; Koch-Nolte, Friedrich; Bannas, Peter.
In: THERANOSTICS, Vol. 10, No. 6, 2020, p. 2645-2658.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Nanobody-based CD38-specific heavy chain antibodies induce killing of multiple myeloma and other hematological malignancies
AU - Schriewer, Levin
AU - Schütze, Kerstin
AU - Petry, Katharina
AU - Hambach, Julia
AU - Fumey, William
AU - Koenigsdorf, Julia
AU - Baum, Natalie
AU - Menzel, Stephan
AU - Rissiek, Björn
AU - Riecken, Kristoffer
AU - Fehse, Boris
AU - Röckendorf, Jana Larissa
AU - Schmid, Joanna
AU - Albrecht, Birte
AU - Pinnschmidt, Hans
AU - Ayuk, Francis
AU - Kröger, Nicolaus
AU - Binder, Mascha
AU - Schuch, Gunter
AU - Hansen, Timon
AU - Haag, Friedrich
AU - Adam, Gerhard
AU - Koch-Nolte, Friedrich
AU - Bannas, Peter
N1 - © The author(s).
PY - 2020
Y1 - 2020
N2 - 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.
AB - 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.
U2 - 10.7150/thno.38533
DO - 10.7150/thno.38533
M3 - SCORING: Journal article
C2 - 32194826
VL - 10
SP - 2645
EP - 2658
JO - THERANOSTICS
JF - THERANOSTICS
SN - 1838-7640
IS - 6
ER -