Engineered antibody Fc variants with enhanced effector function.
Antibody-dependent cell-mediated cytotoxicity, a key effector function for the clinical efficacy of monoclonal antibodies, is mediated primarily through a set of closely related Fcgamma receptors with both activating and inhibitory activities. By using computational design algorithms and high-throughput screening, we have engineered a series of Fc variants with optimized Fcgamma receptor affinity and specificity. The designed variants display >2 orders of magnitude enhancement of in vitro effector function, enable efficacy against cells expressing low levels of target antigen, and result in increased cytotoxicity in an in vivo preclinical model. Our engineered Fc regions offer a means for improving the next generation of therapeutic antibodies and have the potential to broaden the diversity of antigens that can be targeted for antibody-based tumor therapy.
Lazar
Greg A
GA
Xencor, Inc., 111 West Lemon Avenue, Monrovia, CA 91016, USA. glazar@xencor.com
Dang
Wei
W
Karki
Sher
S
Vafa
Omid
O
Peng
Judy S
JS
Hyun
Linus
L
Chan
Cheryl
C
Chung
Helen S
HS
Eivazi
Araz
A
Yoder
Sean C
SC
Vielmetter
Jost
J
Carmichael
David F
DF
Hayes
Robert J
RJ
Dahiyat
Bassil I
BI
D000074323:Alemtuzumab; D000818:Animals; D000911:Antibodies, Monoclonal / Q000235:genetics / Q000378:metabolism; D061067:Antibodies, Monoclonal, Humanized; D000912:Antibodies, Neoplasm / Q000235:genetics / Q000378:metabolism; D000915:Antibody Affinity; D000918:Antibody Specificity; D000920:Antibody-Dependent Cell Cytotoxicity; D000970:Antineoplastic Agents / Q000378:metabolism; D001402:B-Lymphocytes / Q000276:immunology; D003165:Complement System Proteins / Q000378:metabolism; D003602:Cytotoxicity, Immunologic; D014644:Genetic Variation; D006801:Humans; D007141:Immunoglobulin Fc Fragments / Q000235:genetics* / Q000378:metabolism*; D066298:In Vitro Techniques; D008212:Lymphocyte Depletion; D008252:Macaca fascicularis; D015202:Protein Engineering; D017452:Receptors, IgG / Q000378:metabolism; D000068878:Trastuzumab
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000912:Antibodies, Neoplasm; D000970:Antineoplastic Agents; D007141:Immunoglobulin Fc Fragments; D017452:Receptors, IgG; D000074323:Alemtuzumab; D003165:Complement System Proteins; D000068878:Trastuzumab