Bias-less bispecifics

How Merus’ HER2/3 bispecific could succeed in breast cancer where HER3 mAbs failed

Taking a leaf from the small molecule playbook, cancer play Merus N.V. is bringing unbiased screening to the bispecifics space. The biotech is betting the approach can discover bispecific antibodies with novel activity against known targets.

Last week in Cancer Cell, Merus showcased its process and unveiled the mechanism behind its lead candidate MCLA-128, a bispecific against HER2 and HER3.

The data suggest the compound’s unique binding mode at HER2 and potent inhibition of HER3 could overcome the resistance to HER2 monotherapy that other approaches have failed to beat.

According to EVP and CSO Mark Throsby, companies have historically made bispecifics by joining mAbs, or pieces of mAbs, with known activity. Even when companies vet a panel of bispecifics, he said, they typically construct the panel on a narrow range of starting assumptions about the best binding mode and molecular mechanism for the application.

Merus’ strategy is to use a process that has as few in-built assumptions as possible, similar to unbiased screening of small molecules.

Merus casts a wide net by functionally screening hundreds of bispecifics with an array of different characteristics to empirically find the best ones. It also frequently includes searches that can catch more than the main two targets, said Throsby.

“By allowing biology to instruct us about the best combinations of targets and arrangements of binding arms to get the best functional effect, the platform allows us to unlock

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