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DVD-IgG is one type of bispecific antibody format, which is generated from two parental mAbs by placing two variable domains from one parental antibody onto the heavy chain and the light chain of another parental antibody, instead of one variable domain. The variable domain pairs can be derived from whole human, mouse or rat mAbs with phage/yeast display libraries. And the short peptides derived from the N-termini of CH1 or CL link the outer variable domain (VD1) and the inner variable domain (VD2) together. The DVD-IgG retains the antigen-binding specificity, affinity, and biologic activities from its both parental antibodies, therefore, all of its four variable domains are functional. Many different DVD-IgGs have been designed and manufactured for treating complex diseases with multiple mediators contributing to overall disease pathogenesis.