 Juan Carlos Lopez |
 Andy Marshall |
A growing stable of biopharma companies are developing biparatopic antibodies, which hit the same target via two non-overlapping epitopes. Compared with monospecific mAbs, such antibodies display enhanced binding through increased avidity, slower target dissociation, improved internalization, and greater specificity against drug target families where members share significant structural similarity. Now in the Journal of Clinical Investigation, a group at the Broad led by William Sellers describes biparatopic mAbs that inhibit fibroblast growth factor receptor 2 fusions, which are found in a variety of cancers, including intrahepatic cholangiocarcinomas (ICCs).
Sellers and his team showed that their mAbs inhibit signaling through FGFR2 fusions and inhibit ICC proliferation. They generated a panel of 15 biparatopic antibodies from 6 parental human antibodies and systematically tested them for their anti-proliferative activity on cells expressing FGFR2 fusions. Two showed greater potency than the parental antibodies, both in vitro and in vivo. Moreover, these biparatopic antibodies potentiated the action of FGFR2 inhibitors on cancer cells, and their inhibitory effect persisted, even against FGFR2 fusions with mutations that drive drug resistance. Mechanistically, the biparatopic antibodies promoted internalization and lysosomal degradation of FGFR2 fusions.
Sellers is also a scientific founder of Cambridge, Mass-based RedRidge Bio, which was funded in March via an undisclosed Series A venture round. Another recent startup, Attovia, took its first VHH biparatopic nanobody program against IL-31 into the clinic earlier this year and is collaborating with SciNeuro Pharmaceuticals on a neurology target.
The FGFR2 fusion work follows in the footsteps of studies by Regeneron demonstrating that biparatopic antibodies are effective inhibitors of oncogenic fusions of other receptor tyrosine kinases (RTKs). In that work, Regeneron researchers targeted fusions of another FGFR family member, FGFR3. In theory, the approach should be generalizable to any cancer arising from RTK fusions.
Biparatopic antibodies can work either in cis (binding the same target twice) or trans (binding two different molecules of the same target; e.g., to facilitate receptor clustering). Although they have been in clinical testing since 2011, it took until 2022 for the first biparatopic product to reach the market. Nanjing, China-based Legend Biotech (now J&J) got FDA approval for a T-cell therapy against refractory multiple myeloma featuring a chimeric antigen receptor (CAR) based on two single-domain antibodies targeting two different epitopes on B-cell maturation antigen (BCMA). Last November, FDA also gave the green light to Jazz Pharmaceuticals and Zymeworks’s zanidatamab, a biparatopic mAb that binds HER2 in trans and is indicated for patients with HER2-positive biliary tract cancer.
Similar to the antibody drug conjugate (ADC) space, a commercial stampede is currently underway in China to develop biparatopic mAbs against HER2, with at least 4 companies (Xuanzhu Biopharm, Alphamab Oncology, Chia Tai Tianqing Pharmaceutical and Beijing Mabworks) with products in clinical development. Given that big pharma has yet to make major announcements around biparatopic mAbs—notwithstanding AstraZeneca’s/Medimmune’s discontinued effort to develop MEDI4276, an anti HER2 ADC based on a biparatopic scaffold— the recent co-development partnership deal between Pierre Fabre Laboratorie and RedRidge Bio likely augurs more deal activity around this antibody modality in the near future.
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