Antibody targeting of E3 ubiquitin ligases for receptor degradation

Hadir Marei, Wen-Ting K. Tsai, Yee-Seir Kee, Karen Ruiz, Jieyan He, Chris Cox, Tao Sun, Sai Penikalapati, Pankaj Dwivedi, Meena Choi, David Kan, Pablo Saenz-Lopez, Kristel Dorighi, Pamela Zhang, Yvonne T. Kschonsak, Noelyn Kljavin, Dhara Amin, Ingrid Kim, Andrew G. Mancini, Thao Nguyen, Chunling Wang, Eric Janezic, Alexander Doan, Elaine Mai, Hongkang Xi, Chen Gu, Melanie Heinlein, Brian Biehs, Jia Wu, Isabelle Lehoux, Seth Harris, Laetitia Comps-Agrar, Dhaya Seshasayee, Frederic J. de Sauvage, Matthew Grimmer, Jing Li, Nicholas J. Agard () and Felipe de Sousa e Melo ()
Additional contact information
Hadir Marei: Genentech
Wen-Ting K. Tsai: Genentech
Yee-Seir Kee: Genentech
Karen Ruiz: Genentech
Jieyan He: Genentech
Chris Cox: Genentech Inc
Tao Sun: Genentech
Sai Penikalapati: Genentech
Pankaj Dwivedi: Genentech
Meena Choi: Genentech
David Kan: Genentech
Pablo Saenz-Lopez: Genentech
Kristel Dorighi: Genentech
Pamela Zhang: Genentech
Yvonne T. Kschonsak: Genentech
Noelyn Kljavin: Genentech
Dhara Amin: Genentech
Ingrid Kim: Genentech
Andrew G. Mancini: Genentech
Thao Nguyen: Genentech
Chunling Wang: Genentech
Eric Janezic: Genentech
Alexander Doan: Genentech
Elaine Mai: Genentech
Hongkang Xi: Genentech
Chen Gu: Genentech
Melanie Heinlein: Genentech
Brian Biehs: Genentech
Jia Wu: Genentech
Isabelle Lehoux: Genentech
Seth Harris: Genentech
Laetitia Comps-Agrar: Genentech
Dhaya Seshasayee: Genentech
Frederic J. de Sauvage: Genentech
Matthew Grimmer: Genentech
Jing Li: Genentech
Nicholas J. Agard: Genentech
Felipe de Sousa e Melo: Genentech

Nature, 2022, vol. 610, issue 7930, 182-189

Abstract: Abstract Most current therapies that target plasma membrane receptors function by antagonizing ligand binding or enzymatic activities. However, typical mammalian proteins comprise multiple domains that execute discrete but coordinated activities. Thus, inhibition of one domain often incompletely suppresses the function of a protein. Indeed, targeted protein degradation technologies, including proteolysis-targeting chimeras1 (PROTACs), have highlighted clinically important advantages of target degradation over inhibition2. However, the generation of heterobifunctional compounds binding to two targets with high affinity is complex, particularly when oral bioavailability is required3. Here we describe the development of proteolysis-targeting antibodies (PROTABs) that tether cell-surface E3 ubiquitin ligases to transmembrane proteins, resulting in target degradation both in vitro and in vivo. Focusing on zinc- and ring finger 3 (ZNRF3), a Wnt-responsive ligase, we show that this approach can enable colorectal cancer-specific degradation. Notably, by examining a matrix of additional cell-surface E3 ubiquitin ligases and transmembrane receptors, we demonstrate that this technology is amendable for ‘on-demand’ degradation. Furthermore, we offer insights on the ground rules governing target degradation by engineering optimized antibody formats. In summary, this work describes a strategy for the rapid development of potent, bioavailable and tissue-selective degraders of cell-surface proteins.

Date: 2022
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DOI: 10.1038/s41586-022-05235-6

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