Lock-In™ Bispecifics: A Novel Approach To Eliminate Light Chain Mispairing

By Jeffrey Johnson, Joe Barco, Tom Purcell, Deepal Pandya, Rene Pagila, Nahir Rojas Rivera, Mark Welch, Monica Konar, Saketh Chemuru, Divya Vavilala, Tomasz Sosinowski, Renee Saville, Varsha Sitaraman, Calvin Tang, Lynn Webster, Indira Kottayil, Surya Karunakaran, Sridhar Govindarajan, and Jeremy Minshull, ATUM

Common light chain engineering is the usual workaround for mispairing in bispecific development, but it can cost 3 to 12 months and put binding, efficacy, and manufacturability at risk. A different scaffold pairs engineered CH1 and Cμ4 constant regions with knob-in-hole Fc pairing, so discovered antibodies can be tested as discovered rather than reformatted around a shared light chain. The data span a 128-variant matrix built from eight variable regions, with measurements of binding affinity, transient and stable expression, aggregation, and T-cell killing against a benchmark bispecific. Mass spectrometry addresses the central question of whether mispaired species appear at all.

Examine the methods and results to see how the numbers hold up.