Increasing the efficacy of CD20 antibody therapy through the engineering of a new type II anti-CD20 antibody with enhanced direct and immune effector cell-mediated B-cell cytotoxicity.
CD20 is an important target for the treatment of B-cell malignancies, including non-Hodgkin lymphoma as well as autoimmune disorders. B-cell depletion therapy using monoclonal antibodies against CD20, such as rituximab, has revolutionized the treatment of these disorders, greatly improving overall survival in patients. Here, we report the development of GA101 as the first Fc-engineered, type II humanized IgG1 antibody against CD20. Relative to rituximab, GA101 has increased direct and immune effector cell-mediated cytotoxicity and exhibits superior activity in cellular assays and whole blood B-cell depletion assays. In human lymphoma xenograft models, GA101 exhibits superior antitumor activity, resulting in the induction of complete tumor remission and increased overall survival. In nonhuman primates, GA101 demonstrates superior B cell-depleting activity in lymphoid tissue, including in lymph nodes and spleen. Taken together, these results provide compelling evidence for the development of GA101 as a promising new therapy for the treatment of B-cell disorders.
Mössner
Ekkehard
E
GlycArt Biotechnology AG, Schlieren, Switzerland.
Brünker
Peter
P
Moser
Samuel
S
Püntener
Ursula
U
Schmidt
Carla
C
Herter
Sylvia
S
Grau
Roger
R
Gerdes
Christian
C
Nopora
Adam
A
van Puijenbroek
Erwin
E
Ferrara
Claudia
C
Sondermann
Peter
P
Jäger
Christiane
C
Strein
Pamela
P
Fertig
Georg
G
Friess
Thomas
T
Schüll
Christine
C
Bauer
Sabine
S
Dal Porto
Joseph
J
Del Nagro
Christopher
C
Dabbagh
Karim
K
Dyer
Martin J S
MJ
Poppema
Sibrand
S
Klein
Christian
C
Umaña
Pablo
P
D000818:Animals; D000911:Antibodies, Monoclonal / Q000235:genetics* / Q000276:immunology / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized; D058846:Antibodies, Monoclonal, Murine-Derived; D000920:Antibody-Dependent Cell Cytotoxicity; D018951:Antigens, CD20 / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology*; D045744:Cell Line, Tumor; D003602:Cytotoxicity, Immunologic; D005260:Female; D006801:Humans; D007111:Immunity, Cellular; D007141:Immunoglobulin Fc Fragments / Q000235:genetics; D007135:Immunoglobulin Variable Region / Q000235:genetics; D066298:In Vitro Techniques; D008212:Lymphocyte Depletion / Q000379:methods; D016393:Lymphoma, B-Cell / Q000276:immunology / Q000628:therapy; D008228:Lymphoma, Non-Hodgkin / Q000276:immunology / Q000628:therapy; D008252:Macaca fascicularis; D051379:Mice; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D015202:Protein Engineering; D017452:Receptors, IgG / Q000276:immunology; D000069283:Rituximab; D014183:Transplantation, Heterologous
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D058846:Antibodies, Monoclonal, Murine-Derived; D018951:Antigens, CD20; D007141:Immunoglobulin Fc Fragments; D007135:Immunoglobulin Variable Region; D017452:Receptors, IgG; D000069283:Rituximab; C543332:obinutuzumab