Biological action happens when things come together. Proximity matters—a simple but profound fact at the heart of InduPro’s approach to developing new therapeutics. Within the local environment of the cell-surface membrane, proteins can reside as clusters of communities whose proximity is related through direct physical interactions or within co-localized compartments. This inherent proximity of cell-surface proteins is often a key indication of their co-functionality, and so defining the inherent microenvironment of the cell-surface proteome offers new insights into its functional architecture (Fig. 1).
Furthermore, in addition to inherent proximity providing insight into biological action, proximity can be manipulated as a therapeutic paradigm. Conventional therapeutics seek to modify natural ligand/receptor signaling biology. InduPro differentiates through its ‘proximity by design’ approach that utilizes induced proximity via bispecific antibodies to create targeted pairings. These designed cis-interactions of cell-surface proteins provide a new paradigm for affecting therapeutic pathways.
Fig. 1 | Reshaping the architecture of the cell-surface proteome via proximity by design. Defining inherent protein proximity on the cell surface reveals new signaling biology, and identifies opportunities for induced proximity.
Harnessing protein proximity for therapeutics
The potential to leverage cell-surface protein proximity to influence disease-relevant biology has been demonstrated by InduPro’s scientific founder, Chris Garcia, through the manipulation of post-translational modifications. By bringing a phosphatase in close proximity to a phospho-signaling receptor, that signaling pathway can be influenced beyond its inherent ligand signaling biology1,2. Using a bispecific antibody specific for receptors containing immunoreceptor tyrosine activating motif (ITAM), immunoreceptor tyrosine inhibitory motif (ITIM) or immunoreceptor tyrosine-based switch motif (ITSM) as well as the cell-surface phosphatases provides access to a vast amount of signaling biology. Other enzymatic activities, such as ubiquitination via cell-surface associated E3 ligases, can be leveraged to degrade receptors from the cell surface3. This is a generalizable approach to the inhibition of cell-surface signaling beyond typical blockade of ligand signaling.
InduPro is interested in defining inherent proximity to identify unique therapeutic opportunities and using induced proximity in its various forms to create new signaling paradigms and logic gates for cell-surface receptors (Fig. 1). There are multiple proximity paradigms that can be invoked. To be able to explore these concepts, a large set of antibody pairings are needed. Designing binders that induce proximity between target pairs to generate productive target engagement is a combinatorial puzzle. Proximity by design defines the epitopes driving pairing geometry, the spacing between pairs via the bispecific format, and the relative affinities of the binding pairs. This design effort is key to discovering and refining productive induced-proximity pairs.
Supported by protein data
At the heart of InduPro’s proximity by design approach is its industry-leading proximity-discovery toolbox. InduPro has created a proprietary Membrane Interactomics (MInt) database that captures information about naturally, or inherently, proximal surface proteins in disease-relevant systems. An essential component of understanding inherent proximity is InduPro’s microenvironment mapping technology that profiles native protein environments in high resolution with exquisite spatio-temporal control4,5,6. The insights provided by MInt include identifying the most compelling applications of induced proximity, enabling selective dual targeting within tissue environments and cellular subtypes, as well as revealing new biology and therapeutic opportunities. The MInt platform is combined with the ability to broadly create and screen bispecific pairings of antibodies with diverse epitope, affinity and spacing to create optimal molecules.
The platforms driving InduPro’s proximity by design paradigm can be broadly applied to disease biology and therapeutic concepts. InduPro’s vision is to become a clinical-stage biotherapeutic company that addresses patients’ needs through novel proximity-based biologics focused on immunology and oncology.