title: A novel bispecific antibody format enables simultaneous bivalent and monovalent co-engagement of distinct target antigens.
abstract: Bispecific antibodies based on full-length antibody structures are more optimal than fragment-based formats because they benefit from the favorable properties of the Fc region. However, the homodimeric nature of Fc effectively imposes bivalent binding on all current full-length bispecific antibodies, an attribute that can result in nonspecific activation of cross-linked receptors. We engineered a novel bispecific format, referred to as mAb-Fv, that utilizes a heterodimeric Fc region to enable monovalent co-engagement of a second target antigen in a full-length context. mAb-Fv constructs co-targeting CD16 and CD3 were expressed and purified as heterodimeric species, bound selectively to their co-target antigens, and mediated potent cytotoxic activity by NK cells and T cells, respectively. The capacity to co-engage distinct target antigens simultaneously with different valencies is an improved feature for bispecific antibodies with promising therapeutic implications.
authors: Xencor, Inc., Monrovia, CA, USA. gmoore.@xencor.com
authors: Gregory L
authors: GL
authors: Moore
authors: Cristina
authors: C
authors: Bautista
authors: Erik
authors: E
authors: Pong
authors: Duc-Hanh T
authors: DH
authors: Nguyen
authors: Jonathan
authors: J
authors: Jacinto
authors: Araz
authors: A
authors: Eivazi
authors: Umesh S
authors: US
authors: Muchhal
authors: Sher
authors: S
authors: Karki
authors: Seung Y
authors: SY
authors: Chu
authors: Greg A
authors: GA
authors: Lazar
mesh_terms: D000818:Animals; D018033:Antibodies, Bispecific / Q000737:chemistry / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D000920:Antibody-Dependent Cell Cytotoxicity / Q000276:immunology*; D017252:CD3 Complex / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D019281:Dimerization; D057809:HEK293 Cells; D006801:Humans; D007141:Immunoglobulin Fc Fragments / Q000737:chemistry / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D007128:Immunoglobulin Fragments / Q000737:chemistry / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D007694:Killer Cells, Natural / Q000276:immunology; D051379:Mice; D008958:Models, Molecular; D015202:Protein Engineering / Q000379:methods; D017452:Receptors, IgG / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology
chemical_list: D018033:Antibodies, Bispecific; D017252:CD3 Complex; D007141:Immunoglobulin Fc Fragments; D007128:Immunoglobulin Fragments; D017452:Receptors, IgG; C055966:immunoglobulin Fv