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IAP-binding intrabodies for concurrent degradation of proto-oncogenes and toggling cell death modalities

ABSTRACT: Single domain antibodies or antibody mimetics, such as monobodies, can be engineered to degrade undruggable targets via fusion to ubiquitin E3 ligases. In this study we developed multi-targeting biodegrader intrabodies by harnessing an inhibitor of apoptosis (IAP) E3 ligase RING domain, or the IAP-binding motif from SMAC/DIABLO. When fused with monobodies targeting the necroptotic death effector MLKL, IAP-binding intrabodies simultaneously targeted MLKL and IAPs for proteasomal degradation, thereby blocking necroptosis while sensitising cells to apoptosis. The potent degradative capacity of the IAP RING was demonstrated via its fusion to distinct antibody mimetics, with those targeting RAS enabling IAP and RAS proto-oncogenes to be concurrently eliminated. Quantitative proteomics identified that the anti-cancer potential of select IAP-binding intrabodies was due to their removal of the chromatin remodelling BAF complex. Consequently, we show that cancer cells exhibited IAP and BAF co-dependencies, with IAP RING intrabodies prolonging animal survival in an orthotopic breast cancer model. This work positions IAP-binding intrabodies as a novel class of biodegraders, with their multi-targeting capacity enabling the toggling of cell death modalities and eradication of cancer-drivers.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Colorectal Adenocarcinoma Cell Line, Malignant Cell

DISEASE(S): Colon Cancer

SUBMITTER: Maria Tanzer

LAB HEAD: James Vince

PROVIDER: PXD061128 | Pride | 2026-03-03

REPOSITORIES: Pride

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