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Int. J. Mol. Sci. 2015, 16(11), 27497-27507; doi:10.3390/ijms161126037

TriFabs—Trivalent IgG-Shaped Bispecific Antibody Derivatives: Design, Generation, Characterization and Application for Targeted Payload Delivery

Roche Pharma Research & Early Development, Large Molecule Research, Roche Innovation Center Penzberg, D82377 Penzberg, Germany
These authors contributed equally to this work.
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Author to whom correspondence should be addressed.
Academic Editor: Qiang “Shawn” Chen
Received: 12 August 2015 / Revised: 28 October 2015 / Accepted: 5 November 2015 / Published: 17 November 2015
(This article belongs to the Special Issue Protein Engineering)
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Abstract

TriFabs are IgG-shaped bispecific antibodies (bsAbs) composed of two regular Fab arms fused via flexible linker peptides to one asymmetric third Fab-sized binding module. This third module replaces the IgG Fc region and is composed of the variable region of the heavy chain (VH) fused to CH3 with “knob”-mutations, and the variable region of the light chain (VL) fused to CH3 with matching “holes”. The hinge region does not contain disulfides to facilitate antigen access to the third binding site. To compensate for the loss of hinge-disulfides between heavy chains, CH3 knob-hole heterodimers are linked by S354C-Y349C disulphides, and VH and VL of the stem region may be linked via VH44C-VL100C disulphides. TriFabs which bind one antigen bivalent in the same manner as IgGs and the second antigen monovalent “in between” these Fabs can be applied to simultaneously engage two antigens, or for targeted delivery of small and large (fluorescent or cytotoxic) payloads. View Full-Text
Keywords: knob-into-hole; disulfide stabilization; payload delivery; imaging; LeY; GPC3; CD33; saporin knob-into-hole; disulfide stabilization; payload delivery; imaging; LeY; GPC3; CD33; saporin
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MDPI and ACS Style

Mayer, K.; Baumann, A.-L.; Grote, M.; Seeber, S.; Kettenberger, H.; Breuer, S.; Killian, T.; Schäfer, W.; Brinkmann, U. TriFabs—Trivalent IgG-Shaped Bispecific Antibody Derivatives: Design, Generation, Characterization and Application for Targeted Payload Delivery. Int. J. Mol. Sci. 2015, 16, 27497-27507.

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