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.
Xencor, Inc., 111 West Lemon Avenue, Monrovia, CA 91016, USA. glazar@xencor.com
Greg A
GA
Lazar
Wei
W
Dang
Sher
S
Karki
Omid
O
Vafa
Judy S
JS
Peng
Linus
L
Hyun
Cheryl
C
Chan
Helen S
HS
Chung
Araz
A
Eivazi
Sean C
SC
Yoder
Jost
J
Vielmetter
David F
DF
Carmichael
Robert J
RJ
Hayes
Bassil I
BI
Dahiyat
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