Bifunctional immune checkpoint-targeted antibody-ligand traps that simultaneously disable TGFβ enhance the efficacy
Rajani Ravi1, Kimberly A Noonan2, Vui Pham1
1Department of Otolaryngology-Head and Neck Cancer Research, Johns Hopkins University School of Medicine, Baltimore, MD, 21231, USA.
Abstract:
A majority of cancers fail to respond to immunotherapy with antibodies targeting immune checkpoints, such as cytotoxic T-lymphocyte antigen-4 (CTLA-4) or programmed death-1 (PD-1)/PD-1 ligand (PD-L1). Cancers frequently express transforming growth factor-β (TGFβ), which drives immune dysfunction in the tumor microenvironment by inducing regulatory T cells (Tregs) and inhibiting CD8+ and TH1 cells. To address this therapeutic challenge, we invent bifunctional antibody-ligand traps (Y-traps) comprising an antibody targeting CTLA-4 or PD-L1 fused to a TGFβ receptor II ectodomain sequence that simultaneously disables autocrine/paracrine TGFβ in the target cell microenvironment (a-CTLA4-TGFβRIIecd and a-PDL1-TGFβRIIecd). a-CTLA4-TGFβRIIecd is more effective in reducing tumor-infiltrating Tregs and inhibiting tumor progression compared with CTLA-4 antibody (Ipilimumab). Likewise, a-PDL1-TGFβRIIecd exhibits superior antitumor efficacy compared with PD-L1 antibodies (Atezolizumab or Avelumab). Our data demonstrate that Y-traps counteract TGFβ-mediated differentiation of Tregs and immune tolerance, thereby providing a potentially more effective immunotherapeutic strategy against cancers that are resistant to current immune checkpoint inhibitors.
Insights
New bifunctional Y-traps targeting CTLA-4 or PD-L1 and TGFβ show improved cancer immunotherapy efficacy. These novel agents overcome resistance to current immune checkpoint inhibitors by counteracting TGFβ-mediated immune suppression.
Area of Science:
- Oncology
- Immunology
- Biotechnology
Background:
- Many cancers resist current immunotherapies like checkpoint inhibitors (e.g., CTLA-4, PD-1/PD-L1).
- Tumor-expressed transforming growth factor-beta (TGFβ) promotes immune dysfunction by increasing regulatory T cells (Tregs) and suppressing anti-tumor immune cells.
Purpose of the Study:
- To develop novel bifunctional antibody-ligand traps (Y-traps) that simultaneously target immune checkpoints and TGFβ.
- To evaluate the efficacy of these Y-traps against cancer models resistant to existing immunotherapies.
Main Methods:
- Engineered bifunctional antibodies (Y-traps) fusing anti-CTLA-4 or anti-PD-L1 antibodies with a TGFβ receptor II ectodomain.
- Tested Y-traps (a-CTLA4-TGFβRIIecd and a-PDL1-TGFβRIIecd) in preclinical cancer models.
- Compared Y-trap efficacy against respective single-target antibodies (Ipilimumab, Atezolizumab, Avelumab).
Main Results:
- Y-traps effectively neutralized TGFβ signaling within the tumor microenvironment.
- a-CTLA4-TGFβRIIecd demonstrated superior reduction of tumor-infiltrating Tregs and tumor progression inhibition compared to Ipilimumab.
- a-PDL1-TGFβRIIecd showed enhanced antitumor efficacy versus Atezolizumab and Avelumab.
Conclusions:
- Bifunctional Y-traps counteract TGFβ-driven immune suppression and tolerance.
- These novel therapeutics offer a promising strategy for overcoming resistance to current immune checkpoint inhibitors in cancer treatment.
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