# In vivo efficacy, safety and PK/PD analysis of SYN101, a first in class, immune cell targeted TGFb therapy for cancer patients

> **NIH NIH R44** · SYNTHIS THERAPEUTICS, INC. · 2024 · $578,977

## Abstract

NCI SBIR Phase II Summary
 The immune checkpoint inhibitors (ICI) block a single immuno-suppressive pathway in cancer patients.
However, across all cancers, less than 30% of patients respond to ICI therapies, due to additional brakes on
the immune system, which limit efficacy. The immuno-suppressive cytokine, TGF− is one of those “brakes”
that drives checkpoint resistance in multiple solid tumors such as colorectal, bladder, prostate, head and neck
cancers and melanoma. Levels of TGF− increase as the cancer becomes more aggressive, driving a worse
patient prognosis. In addition to maintaining tissue health and homeostasis, TGF− is a validated tumor
promoting cytokine with has multiple roles in cancer development, including immune suppression, increasing
angiogenesis and driving metastasis. Despite long standing interest in TGF− blockade as a cancer therapy,
clinical development has been hampered for two main reasons: 1) significant host (i.e., cardiac) toxicity and 2)
the potential to convert indolent early stage tumors into more aggressive ones. However, in preclinical studies,
blockade of the TGF− pathway only in T cells is sufficient for tumor clearance in vivo. Thus, a therapy that
eliminates TGF− signaling solely in immune cells would drive tumor clearance, while avoiding the adverse
events demonstrated by systemic TGF− therapies. With both a Phase I SBIR grant and venture funding, we
have generated SYN101, a proprietary immune cell targeted TGF- therapeutic (SYN101) that selectively
reverses TGF- mediated immune suppression, while sparing host tissue toxicity. We have demonstrated that
monotherapy SYN101 drives tumor clearance and survival in syngeneic mouse tumor models, with
corresponding immune cell activation markers in the blood and tumor microenvironment. Moreover, SYN101
does not cause cardiac toxicity at efficacious doses in vivo. In this Phase II SBIR application, we will perform
additional in vivo efficacy, safety and PK studies with our SYN101 development candidate, which will lead to
IND enabling studies. In Aim 1, we will test efficacy of human SYN101 in humanized mouse tumor models,
along with corresponding lymphocyte PD markers in the blood and tumor microenvironment. Using CyTOF
analysis, we will define the comprehensive immune response driven by SN101 in vivo, as a step towards
identifying biomarkers of TGF- target engagement in clinical trials. In Aim 2, we will test the safety and toxicity
of SYN101 in Sprague Dawley rats, the industry standard for systemic TGF- inhibitor toxicity. In addition, we
will perform PK studies, to round out the full preclinical data package. While we do not anticipate significant
toxicity from SYN101, these studies will derisk the platform, establish efficacy and safety, and support entry
into IND enabling. Virtually every advanced tumor has elevated TGF− levels, such that a safer, more
efficacious targeted TGF- therapy would be beneficial for a significant portion of cancer patie...

## Key facts

- **NIH application ID:** 11007948
- **Project number:** 1R44CA291368-01A1
- **Recipient organization:** SYNTHIS THERAPEUTICS, INC.
- **Principal Investigator:** Dori A Thomas-Karyat
- **Activity code:** R44 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $578,977
- **Award type:** 1
- **Project period:** 2024-09-18 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11007948

## Citation

> US National Institutes of Health, RePORTER application 11007948, In vivo efficacy, safety and PK/PD analysis of SYN101, a first in class, immune cell targeted TGFb therapy for cancer patients (1R44CA291368-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/11007948. Licensed CC0.

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