bispecifics, are a class of engineered antibody and antibody-like proteins that can simultaneously bind to two different targets, have shown promise as next generation biotherapeutics. their potential lies in delivering a drug with two payloads, instead of one, and also the flexibility of creating antibodies with different pairs of targets to address multitudes of treatments. however, large-scale manufacturing of bispecific biologics is more complex than regular antibody production, often ending up with low yield, aggregated or unstable products. this has posed a great challenge for the bispecifics field and has limited the development of bispecific drugs in the past two decades, with only two approved bispecific drugs on the market today.
adjust multiple different interactions
break down homodimer interaction
no in vitro reconstitution – straightforward production
through years of research, we have developed a world-class fc -based heterodimer bispecific platform called crib (charge repulsion induced bispecific) to overcome cmc (chemistry, manufacturing and control) issues for fc based bispecifics. it is our belief that the closer the structure of a bispecific is to a natural antibody, the better for manufacturing of bispecifics. the crib platform enables the formation of a bispecific antibody with identical format and size of a regular antibody.
the crib technology represents the 3rd generation of fc-based bispecific platforms in engineering the fc domain of antibodies. to favor heterodimerization over homodimerization of the fc, crib has introduced point mutations to induce changes in charge and hydrogen-bond interactions, in addition to steric interactions (knob-in-hole). the crib platform has been well validated by our her2 bispecific candidate kn026*, which retains all the desirable features of a regular antibody, such as high yield at large-scale (3 g/l or above) standard production, full antibody function, and a stable product.
* wei h, cai h, jin y, et al. structural basis of a novel heterodimeric fc for bispecific antibody production. oncotarget, 2017, 8(31): 51037.