# Strategies for Receptor inhibition in immunotherapy

> **NIH NIH R01** · STANFORD UNIVERSITY · 2022 · $367,811

## Abstract

Abstract:
Despite the recent advances in immunotherapy, such as checkpoint blockade, radical new approaches are
needed to both improve the efficacy of existing treatments, and to offer entirely new therapeutic modalities. In
the previous term of this award we developed an immunotherapeutic agent that exploited the myeloid branch of
the immune system by blocking the SIRPa/CD47 axis, potentiating macrophage attack on tumors. We
engineered a unique, high-affinity SIRPa antagonist of CD47 that greatly potentiated the anti-tumor efficacy of
several clinically approved anti-tumor antibodies, yet offered the advantage of being tumor selective and non-
toxic, which is a limitation of most current anti-CD47 mAbs. This molecule is now in clinical trials for several
cancer types, thus completing the cycle of bench to bedside in one term of the award. In this renewal application,
we request support to develop a new paradigm for receptor inhibition in oncology. We present a new approach
to immune checkpoint blockade (ICB), and antagonizing the CD47/SIRPa axis, by exploiting an untapped
natural biological mechanism for dampening immune receptor signaling. We have found that
ITIM/ITAM/ITSM/ITTM-containing immunoreceptors, such as the checkpoint receptors PD1 and CTLA4, tonically
signal in the absence of ligand engagement. As a result, blocking PD-L1 binding with anti-PD1 antibodies, does
not fully “take the brakes off” of T cell activation: ligand-independent PD1 tonic signaling significantly blunts
T cell activation. We have devised a strategy reduce or eliminate tonic signaling, termed Receptor Inhibition by
Phosphatase Recruitment (RIPR), that relies on the cis-ligation of kinases-mediated signaling receptors to a cell
surface phosphatase, such as CD45, to achieve complete signal inhibition through intracellular
dephosphorylation of the target receptor intracellular ITAM/ITIM/ITSM/ITTM domains. RIPR molecules are bi-
specific antibodies that compel dimerization of a target receptor to a cell-surface phosphatase, inhibiting both
ligand binding and tonic signaling. Using the PD1 system as our first target, we find that we achieve significantly
greater inhibition of checkpoint blockade using a RIPR that dimerizes PD1 with the T cell phosphatase CD45,
versus ligand blocking by anti-PD1 antibodies. Furthermore, we see enhanced therapeutic efficacy over anti-
PD1 in several mouse tumor models. In this proposal we seek support to better understand the mechanism of
RIPR at the biochemical and cellular level, to assess its therapeutic efficacy in a range of mouse tumor models
both alone and in combination with therapeutic antibodies, and to explore RIPR applications beyond checkpoint
inhibition to other receptors, such as CTLA4 and SIRPa, that are oncology drug targets.

## Key facts

- **NIH application ID:** 10379372
- **Project number:** 5R01CA177684-07
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Michael Lawrence Dougan
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $367,811
- **Award type:** 5
- **Project period:** 2014-05-01 → 2026-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10379372

## Citation

> US National Institutes of Health, RePORTER application 10379372, Strategies for Receptor inhibition in immunotherapy (5R01CA177684-07). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10379372. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*