Type I CD20 Antibodies Recruit the B Cell Receptor for Complement-Dependent Lysis of Malignant B Cells.
Human IgG1 type I CD20 Abs, such as rituximab and ofatumumab (OFA), efficiently induce complement-dependent cytotoxicity (CDC) of CD20+B cells by binding of C1 to hexamerized Fc domains. Unexpectedly, we found that type I CD20 Ab F(ab')2fragments, as well as C1q-binding-deficient IgG mutants, retained an ability to induce CDC, albeit with lower efficiency than for whole or unmodified IgG. Experiments using human serum depleted of specific complement components demonstrated that the observed lytic activity, which we termed "accessory CDC," remained to be dependent on C1 and the classical pathway. We hypothesized that CD20 Ab-induced clustering of the IgM or IgG BCR was involved in accessory CDC. Indeed, accessory CDC was consistently observed in B cell lines expressing an IgM BCR and in some cell lines expressing an IgG BCR, but it was absent in BCR-B cell lines. A direct relationship between BCR expression and accessory CDC was established by transfecting the BCR into CD20+cells: OFA-F(ab')2fragments were able to induce CDC in the CD20+BCR+cell population, but not in the CD20+BCR-population. Importantly, OFA-F(ab')2fragments were able to induce CDC ex vivo in malignant B cells isolated from patients with mantle cell lymphoma and Waldenström macroglobulinemia. In summary, accessory CDC represents a novel effector mechanism that is dependent on type I CD20 Ab-induced BCR clustering. Accessory CDC may contribute to the excellent capacity of type I CD20 Abs to induce CDC, and thereby to the antitumor activity of such Abs in the clinic.
Genmab, 3584 CM Utrecht, the Netherlands.
Patrick J
0000-0002-6274-8554
PJ
Engelberts
Genmab, 3584 CM Utrecht, the Netherlands.
Marleen
M
Voorhorst
Genmab, 3584 CM Utrecht, the Netherlands.
Janine
0000-0002-9738-9926
J
Schuurman
Department of Hematology, University Medical Center Groningen, 9713 GZ Groningen, the Netherlands.
Tom
0000-0002-5581-6950
T
van Meerten
Genmab, 3584 CM Utrecht, the Netherlands.
Joost M
JM
Bakker
Genmab, 3584 CM Utrecht, the Netherlands.
Tom
0000-0001-6205-1733
T
Vink
Genmab, 3584 CM Utrecht, the Netherlands.
Wendy J M
WJ
Mackus
Genmab, 3584 CM Utrecht, the Netherlands.
Esther C W
0000-0002-5368-6849
EC
Breij
Division of Stem Cell Transplantation and Immunotherapy, 2nd Department of Medicine, Christian Albrechts University, 24105 Kiel, Germany.
Stefanie
0000-0002-6142-5577
S
Derer
Division of Stem Cell Transplantation and Immunotherapy, 2nd Department of Medicine, Christian Albrechts University, 24105 Kiel, Germany.
Thomas
0000-0001-9181-8067
T
Valerius
Genmab, 3584 CM Utrecht, the Netherlands.|Department of Immunology, University Medical Center Utrecht, 3584 EA Utrecht, the Netherlands.
Jan G J
JG
van de Winkel
Genmab, 3584 CM Utrecht, the Netherlands; P.Parren@genmab.com.|Department of Cancer and Inflammation Research, Institute of Molecular Medicine, University of Southern Denmark, 5000 Odense, Denmark; and.|Department of Hematology and Blood Transfusion, Leiden University Medical Center, 2333 ZA Leiden, the Netherlands.
Paul W H I
0000-0002-4365-3859
PW
Parren
Genmab, 3584 CM Utrecht, the Netherlands.
Frank J
0000-0002-7165-5771
FJ
Beurskens
D000911:Antibodies, Monoclonal / Q000235:genetics / Q000378:metabolism* / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized; D000920:Antibody-Dependent Cell Cytotoxicity; D018951:Antigens, CD20 / Q000276:immunology / Q000378:metabolism*; D001402:B-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D045744:Cell Line, Tumor; D003172:Complement C1 / Q000378:metabolism; D003171:Complement Pathway, Classical; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000378:metabolism; D007074:Immunoglobulin G / Q000235:genetics / Q000378:metabolism; D007075:Immunoglobulin M / Q000235:genetics / Q000378:metabolism; D016219:Immunotherapy, Adoptive / Q000379:methods*; D016393:Lymphoma, B-Cell / Q000276:immunology / Q000628:therapy*; D011947:Receptors, Antigen, B-Cell / Q000235:genetics / Q000378:metabolism; D000069283:Rituximab / Q000235:genetics / Q000378:metabolism* / Q000627:therapeutic use
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D018951:Antigens, CD20; D003172:Complement C1; D007140:Immunoglobulin Fab Fragments; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D011947:Receptors, Antigen, B-Cell; D000069283:Rituximab; C527517:ofatumumab