Fc Technology
- Bispecific Fc Domain
- Cytotoxic Fc Domain
- Immune Inhibitor Fc Domain
- Xtend™ Fc Domain
- XmAb® Core Technology
- Reviews
Bispecific Fc Domain
Moore, G.L., Bautista, C., Pong, E., Nguyen, D.H., Jacinto, J., Eivazi, A., Muchhal, U.S., Karki, S., Chu, S.Y., and Lazar, G.A. 2011. A novel bispecific antibody format enables simultaneous bivalent and monovalent co-engagement of distinct target antigens. mAbs 3(6): 546-557
Chu, S. Y., Lee, S., Rashid, R., Chen, H., Chan, E. W., Phung, S., Pong, E., Endo, N. A., Miranda, Y., Bonzon, C., Leung, I. W., Muchhal, U. S., Moore, G. L., Bernett, M. J., Szymkowski, D. E., and Desjarlais, J. R. 2014. Immunotherapy with long-lived anti-CD20 × anti-CD3 bispecific antibodies stimulates potent T cell-mediated killing of human B cell lines and of circulating and lymphoid B cells in monkeys: a potential therapy for B cell lymphomas and leukemias. Blood 124(21), 3111
Chu, S. Y., Miranda, Y., Phung, S., Chen, H., Rashid, R., Endo, N. A., Chan, E. W., Pong, E., Bonzon, C., Muchhal, U. S., Leung, I. W., Bernett, M. J., Moore, G. L., Szymkowski, D. E., and Desjarlais, J. R. 2014. Immunotherapy with long-lived anti-CD38 × anti-CD3 bispecific antibodies stimulates potent T cell-mediated killing of human myeloma cell lines and CD38+ cells in monkeys: a potential therapy for multiple myeloma. Blood (poster) 124(21), 4727
Chu, S. Y., Pong, E., Chen, H., Phung, S., Chan, E. W., Endo, N. A., Rashid, R., Bonzon, C., Leung, I. W., Muchhal, U. S., Moore, G. L., Bernett, M. J., Szymkowski, D. E., and Desjarlais, J. R. 2014. Immunotherapy with long-lived anti-CD123 × anti-CD3 bispecific antibodies stimulates potent T cell-mediated killing of human AML cell lines and of CD123+ cells in monkeys: a potential therapy for acute myelogenous leukemia. Blood 124(21), 2316
Moore, G. L., Lee, S., Schubbert, S., Miranda, Y., Rashid, R., Pong, E., Phung, S., Chan, E. W., Chen, H., Endo, N., Ardila, M. C., Bernett, M. J., Chu, S., Leung, I. W., Muchhal, U., Bonzon, C., Szymkowski, D. E., and Desjarlais, J. 2015. Tuning T cell affinity improves efficacy and safety of anti-CD38 × anti-CD3 bispecific antibodies in monkeys – a potential therapy for multiple myeloma. Blood (poster) 126(23), 1798
Chu, S.Y., Pong, E., Schubbert, S., Rashid, R., Chen, S., Chan, E., Phung, S., Endo, N.A., Ardilla, M.C., Bonzon, C., Leung, I.W.L., Muchhal, U.S., Moore, G.L., Bernett, M.J., Avery, K.A., Desjarlais, J.R. and Szymkowski, D.E. 2016. Immunotherapy with anti-PSMA x anti-CD3 bispecific antibody stimulates potent killing of a human prostate cancer cell line and target-mediated T cell activation in monekys: a potential therapy for prostate cancer. Cancer Res 76(14)Suppl
Bernett, M.J., Bonzon, C., Rashid, R., Varma, R., Avery, K.N, Leung. I.W.L., Chu. S.Y., Muchhal, U.S., Moore, G.L., and Desjarlais, J.R. 2017. IL15/IL15Rα heterodimeric Fc-fusions with extended half-lives. AACR Annual Meeting IL15/IL15Rα
Lee, S-H., Chu, S.Y., Rashid, R., Phung, S., Leung, I., Muchhal, U.S., Moore, G.L., Bernett, M.J., Schubbert, S., Ardila, C., Bonzon, C., Foster, P., Szymkowski, D.E., and Desjarlais, J.R. 2017. Anti-SSTR2 × anti-CD3 bispecific antibody induces potent killing of human tumor cells in vitro and in mice, and stimulates target-dependent T cell activation in monkeys: a potential immunotherapy for neuroendocrine tumors. AACR Annual Meeting (poster)
Moore, G.L., Hedvat, M., Bernett, M.J., Varma, R., Schubbert, S., Bonzon, C., Avery, K.A., Rashid, R., Nisthal, A., Bogaert, L., Leung, I.W.L., Chu, S.Y., Muchhal, U.S., and Desjarlais, J.R. 2017. Combination of PD1 blockade and T cell costimulation by bispecific antibodies promotes human T cell activation and proliferation. AACR Annual Meeting (poster)
Nisthal, A., Bernett, M.J., Moore, G.L., Hedvat, M., Bonzon, C., Chu, S.Y., Rashid, R., Avery, K., Umesh, U.S. and Desjarlais, J.R. 2016. Mulitple bispesific combinations promote T cell activation. IBC’s Antibody Engineering & Therapeutics Conference (poster)
Moore, G.L., Bernett, M.J., Rashid, R., Pong, E.W., Nguyen, D.H., Jacinto, J., Eivazi, A., Nisthal, A., Diaz, J.E., Chu, S.Y., Muchhal, U.S. and Desjarlais, J.R. 2019. A robust heterodimeric Fc platform engineered for efficient development of bispecific antibodies of multiple formats. Methods. 154:38-50
Cytotoxic Fc Domain
Lazar, G.A., Dang, W., Karki, S., Vafa, O., Peng, J.S., Hyun, L., Chan, C., Chung, H.S., Eivazi, A., Yoder, S.C., Vielmetter, J., Carmichael, D.F., Hayes, R.J., and Dahiyat, B.I. 2006 Engineered antibody Fc variants with enhanced effector function. PNAS 103(11), 4005-4010
Lawrence, C. E., Hammond, P. W., Zalevsky, J., Horton, H., Chu, S., Karki, S., Desjarlais, J. R., and Carmichael, D. F. 2007 XmAb™2513, an Fc engineered humanized anti-CD30 monoclonal antibody, has potent in vitro and in vivo activities, and has the potential for treating hematologic malignancies. Blood (poster) 110(11), 2340
Horton, H.M., Bernett, M.J., Pong, E., Peipp, M., Karki, S., Chu, S.Y., Richards, J.O., Vostiar, I., Joyce, P.F., Repp, R., Desjarlais, J.R., and Zhukovsky, E.A. 2008 Potent in vitro and in vivo activity of an Fc-engineered anti-CD19. Cancer Res 68(19):8049-8057
Lawrence, C. E., Zalevsky, J., Horton, H., Leung, I., Chu, S., Karki, S., Zhukovsky, E., Desjarlais, J. R., & Carmichael, D. F. 2008 XmAb®5574, an Fc engineered humanized anti-CD19 monoclonal antibody, has potent in vitro and in vivo activities, and has the potential for treating B cell malignancies. Blood (poster) 112(11), 2621
Zalevsky, J., Leung, I.W., Karki, S., Chu, S.Y., Zhukovsky, E.A., Desjarlais, J.R., Carmichael, D.F., and Lawrence, C.E. 2009 The impact of Fc engineering on an anti-CD19 antibody: increased Fcγ receptor affinity enhances B-cell clearing in nonhuman primates. Blood 113:3735-3743
Awan, F.T., Lapalombella, R., Trotta, R., Butchar, J.P., Yu, B., Benson, D.M., Roda, J.M., Cheney, C., Mo, X., Lehman, A., Jones, J., Flynn, J., Jarjoura, D., Desjarlais, J.R., Tridandapani, S., Caligiuri, M.A., Muthusamy, N., and Byrd, J.C. 2010 CD19 targeting of chronic lymphocytic leukemia with a novel Fc-domain–engineered monoclonal antibody. Blood 115(6): 1204-1213
Horton, H. M., Bernett, M. J., Peipp, M., Pong, E., Karki, S., Chu, S. Y., Richards, J. O., Chen, H., Repp, R., Desjarlais, J. R., and Zhukovsky, E. A. 2010 Fc-engineered anti-CD40 antibody enhances multiple effector functions and exhibits potent in vitro and in vivo antitumor activity against hematologic malignancies. Blood 116(16), 3004-3012
Kellner, C., Zhukovsky, E.A., Pötzke, A., Brüggemann, M., Schrauder, A., Schrappe, M., Kneba, M., Repp, R., Humpe, A., Gramatzki, M., and Peipp, M. 2013 The Fc-engineered CD19 antibody MOR208 (XmAb5574) induces natural killer cell-mediated lysis of acute lymphoblastic leukemia cells from pediatric and adult patients. Leukemia 27:1595-1598
Woyach, J.A., Awan, F., Flinn, I.W., Berdeja, J.G., Wiley, E., Mansoor, S., Huang, Y., Lozanski, G., Foster, P.A., and Byrd, J.C. 2014 A phase I trial of the Fc engineered CD19 antibody XmAb®5574(MOR00208) demonstrates safety and preliminary efficacy in relapsed chronic lymphocytic leukemia. Blood 124(24): 3553–3560
Immune Inhibitor Fc Domain
Chu, S.Y., Vostiar, I., Karki, S., Moore, G.L., Lazar, G.A., Pong, E., Joyce, P.F., Szymkowski, D.E., and Desjarlais, J.R. 2008 Inhibition of B cell receptor-mediated activation of primary human B cells by coengagement of CD19 and FcγRIIb with Fc-engineered antibodies. Mol Immunol 45(15):3926-33
Horton, H.M., Chu, S.Y., Ortiz, E.C., Pong, E., Cemerski, S., Leung, I.W., Jacob, N., Zalevsky, J., Desjarlais, J.R., Stohl, W., and Szymkowski, D.E. 2011 Antibody-mediated coengagement of FcγRIIb and B cell receptor complex suppresses humoral immunity in systemic lupus erythematosus. J Immunol 186(7):4223-33
Chu, S.Y., Yeter, K., Kotha, R., Pong, E., Miranda, Y., Phung, S., Chen, H., Lee, S.H., Leung, I., Bonzon, C., Desjarlais, J.R., Stohl, W., and Szymkowski, D.E. 2014 Suppression of rheumatoid arthritis B cells by XmAb5871, an anti-CD19 antibody that coengages B cell antigen receptor complex and Fcγ receptor IIb inhibitory receptor. Arthritis Rheumatol 66(5):1153-64
Szili, D., Cserhalmi, M., Bankó, Z., Nagy, G., Szymkowski, D.E., and Sármay, G. 2014 Suppression of innate and adaptive B cell activation pathways by antibody coengagement of FcγRIIb and CD19. mAbs 6(4):991-999
Xtend™ Fc Domain
Zalevsky, J., Chamberlain, A.K., Horton, H.M., Karki, S., Leung, I.W., Sproule, T.J., Lazar, G.A., Roopenian, D.C., and Desjarlais, J.R. 2010 Enhanced antibody half-life improves in vivo activity. Nat Biotechnol 28(2):157-9
Bernett, M.J., Chu, S.Y., Leung, I., Moore, G.L., Lee, S.H., Pong, E., Chen, H., Phung, S., Muchhal, U.S., Horton, H.M., Lazar, G.A., Desjarlais, J.R., and Szymkowski, D.E. 2013 Immune suppression in cynomolgus monkeys by XPro9523: an improved CTLA4-Ig fusion with enhanced binding to CD80, CD86 and neonatal Fc receptor FcRn. mAbs 5(3):384-96
Saunders, K.O., Pegu, A., Georgiev, I.S., Zeng, M., Joyce, M.G., Yang, Z.Y., Ko, S.Y., Chen, X., Schmidt, S.D., Haase, A.T., Todd, J.P., Bao, S., Kwong, P.D., Rao, S.S., Mascola, J.R., and Nabel, G.J. 2015 Sustained delivery of a broadly neutralizing antibody in nonhuman primates confers long-term protection against simian/human immunodeficiency virus infection. J. Virol. 89(11):5895-5903
Nnane, I.P., Han, C., Jiao, Q., Tam, S.H., Davis, H.M., and Xu, Z. 2017 Modification of the Fc region of a human anti-oncostatin M monoclonal antibody for higher affinity to FcRn receptor and extension of half-life in cynomolgus monkeys. Basic Clin Pharmacol Toxicol doi:10.1111/bcpt.12761
XmAb® Core Technology
Lazar, G.A., Desjarlais, J.R., Jacinto, J., Karki, S., and Hammond P.W. 2007 A molecular immunology approach to antibody humanization and functional optimization. Mol Immunol 44, 1986-1998
Bernett, M.J., Karki, S., Moore, G.L., Leung, I.W., Chen, H., Pong, E., Nguyen, D.H., Jacinto, J., Zalevsky, J., Muchhal, U.S., Desjarlais, J.R., and Lazar, G.A. 2008 Engineering fully human monoclonal antibodies from murine variable regions. J Mol Biol 396(5):1474-90
Richards, J.O., Karki, S., Lazar, G.A., Chen, H., Dang, W., and Desjarlais, J.R. 2008 Optimization of antibody binding to FcγRIIa enhances macrophage phagocytosis of tumor cells. Mol Cancer Ther 7(8):2517-27
Moore, G.L., Chen, H., Karki, S., and Lazar, G.A. 2010 Engineered Fc variant antibodies with enhanced ability to recruit complement and mediate effector functions. mAbs 2(2):181-189
Cemerski, S., Chu, S.Y., Moore, G.L., Muchhal, U.S., Desjaralis, J.R., and Szymkowski, D.E. 2012 Suppression of mast cell degranulation through a dual-targeting tandem IgE–IgG Fc domain biologic engineered to bind with high affinity to FcγRIIb. Immunol Lett 143(1):34-43
Reviews
Desjarlais, J.R., Lazar, G.A., Zhukovsky, E.A., and Chu, S.Y. 2007. Optimizing engagement of the immune system by anti-tumor antibodies: an engineer’s perspective. Drug Discov Today 12(21-22): 898-910
Desjarlais, J.R., and Lazar, G.A. 2011. Modulation of antibody effector function. Exp Cell Res 317(9)1278-1285
Sondermann, P., and Szymkowksi, D.E. 2016. Harnessing Fc receptor biology in the design of therapeutic antibodies. Curr Opin Immunol 40:78-87
Clynes, R.A. and Desjarlais, J.R. 2019. Redirected T cell cytotoxicity in cancer therapy. Annu Rev Med. 70:437-450