The use of CrossMAb technology for the generation of bi- and multispecific antibodies.
The major challenge in the generation of bispecific IgG antibodies is enforcement of the correct heavy and light chain association. The correct association of generic light chains can be enabled using immunoglobulin domain crossover, known as CrossMAb technology, which can be combined with approaches enabling correct heavy chain association such as knobs-into-holes (KiH) technology or electrostatic steering. Since its development, this technology has proven to be very versatile, allowing the generation of various bispecific antibody formats, not only heterodimeric/asymmetric bivalent 1+1 CrossMAbs, but also tri- (2+1), tetravalent (2+2) bispecific and multispecific antibodies. Numerous CrossMAbs have been evaluated in preclinical studies, and, so far, 4 different tailor-made bispecific antibodies based on the CrossMAb technology have entered clinical studies. Here, we review the properties and activities of bispecific CrossMAbs and give an overview of the variety of CrossMAb-enabled antibody formats that differ from heterodimeric 1+1 bispecific IgG antibodies.
a Roche Innovation Center Zurich , Roche Pharmaceutical Research & Early Development, Wagistrasse , Schlieren , Switzerland.
Christian
C
Klein
b Roche Innovation Center Munich , Roche Pharmaceutical Research & Early Development, Nonnenwald , Penzberg , Germany.
Wolfgang
W
Schaefer
b Roche Innovation Center Munich , Roche Pharmaceutical Research & Early Development, Nonnenwald , Penzberg , Germany.
Jörg T
JT
Regula
D018033:Antibodies, Bispecific / Q000737:chemistry / Q000276:immunology*; D000911:Antibodies, Monoclonal / Q000276:immunology; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000276:immunology; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000737:chemistry / Q000276:immunology; D007074:Immunoglobulin G / Q000737:chemistry / Q000276:immunology*; D015202:Protein Engineering / Q000379:methods*; D055503:Protein Multimerization; D055672:Static Electricity
D018033:Antibodies, Bispecific; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D007140:Immunoglobulin Fab Fragments; D007074:Immunoglobulin G; C000619444:vanucizumab
2+1, 1+1; 2+2; Ang-2; CEA TCB; CrossMAb; DAF-CrossMAb; DVD-CrossMAb; DuoMAb; EGFR; HER1; HER3; Immunoglobulin domain crossover; Kappa-Lambda-CrossMAb; MoAb; MoAb-Dimer; MonoMAb; P329G LALA; RG7221; RG7386; RG7716; RG7802; Triple A; VEGF-A; asymmetric; heterodimeric; knobs-into-holes (KiH); vanucizumab