Hetero H, forced HL IgG1/ DuetMab

Hetero H, forced HL IgG1/ DuetMab replaces the native disulfide bond in the CH1-CL interface with an engineered disulfide bond (fig. 1). This enhances cognate light chain pairing. Three different positions in the CH1-CL interface are possible candidates for favoring the formation of a novel disulfide bond. An amino acid on the HC and one on the LC is replaced with cysteine in one of the Fab regions. The native disulfide bond on the other Fab region is left intact. It is advantageous that the modifications are in the CH1-CL interface and not in the variable domain, as this could have detrimental effects on antigen binding. Although, engineering in the CH1-CL interface could mean that κ and λ constant light chains would somehow affect the usefulness of this approach. However, it was shown to be compatible to both isotypes (Mazor et al. 2015). DuetMab could be generically applied to bispecific antibodies in development since the approach: (i) does not contain variable domain engineering, (ii) is compatible with both kappa and lambda isotypes and (iii) was able to induce correct heterodimerization.

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Fig. 1. Schematic diagram to differentiate conventional monospecific mAbs (antibodies A and B) from DuetMab. The DuetMab is comprised of one wild-type Fab and one engineered Fab with the interchain disulfide redesigned (in red) within the CH1-CL interface. The yellow star on the hole heavy chain represents the RF mutation to ablate protein A binding. (Adopted from: Mazor, Y., Oganesyan, V., Yang, C., Hansen, A., Wang, J., Liu, H., Sachsenmeier, K., Carlson, M., Gadre, D.V., Borrok, M.J., Yu, X.Q., Dall'Acqua, W., Wu, H., Chowdhury, P.S. (2015) Improving target cell specificity using a novel monovalent bispecific IgG design. MAbs. 7(2):377-89.)



Formats of bispecific antibodies (BsAbs)

Many formats have been developed for BsAb generation as listed in the following table.





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