A Novel d-Peptide Identified by Mirror-Image Phage Display Blocks TIGIT/PVR for Cancer Immunotherapy
Xiuman Zhou1, Chao Zuo2, Wanqiong Li3
1School of Life Sciences, Zhengzhou University, Zhengzhou, 450001, China.
Abstract:
The low response rate and adaptive resistance of PD-1/PD-L1 blockade demands the studies on novel therapeutic targets for cancer immunotherapy. We discovered that a novel immune checkpoint TIGIT expressed higher than PD-1 in many tumors especially anti-PD-1 resistant tumors. Here, mirror-image phage display bio-panning was performed using the d-enantiomer of TIGIT synthesized by hydrazide-based native chemical ligation. d-peptide D TBP-3 was identified, which could occupy the binding interface and effectively block the interaction of TIGIT with its ligand PVR. D TBP-3 showed proteolytic resistance, tumor tissue penetrating ability, and significant tumor suppressing effects in a CD8+ T cell dependent manner. More importantly, D TBP-3 could inhibit tumor growth and metastasis in anti-PD-1 resistant tumor model. This is the first d-peptide targeting TIGIT, which could serve as a potential candidate for cancer immunotherapy.
Insights
A novel d-peptide, D TBP-3, effectively blocks the TIGIT immune checkpoint, showing promise for cancer immunotherapy, especially in tumors resistant to PD-1/PD-L1 blockade.
Area of Science:
- Immunology
- Oncology
- Drug Discovery
Background:
- Immune checkpoint inhibitors like PD-1/PD-L1 blockade have limitations due to low response rates and adaptive resistance.
- TIGIT is an emerging immune checkpoint that is upregulated in various tumors, particularly those resistant to PD-1/PD-L1 therapy.
Purpose of the Study:
- To identify and develop a novel therapeutic agent targeting the TIGIT immune checkpoint.
- To evaluate the efficacy of the developed agent in preclinical cancer models, including anti-PD-1 resistant tumors.
Main Methods:
- Mirror-image phage display bio-panning was employed using a d-enantiomer of TIGIT.
- Hydrazide-based native chemical ligation was used for d-peptide synthesis.
- The efficacy of the identified d-peptide (D TBP-3) was assessed in vitro and in vivo, including its pharmacokinetic properties and anti-tumor effects in CD8+ T cell-dependent models.
Main Results:
- A novel d-peptide, D TBP-3, was identified that binds to TIGIT and blocks its interaction with PVR.
- D TBP-3 demonstrated proteolytic resistance, tumor tissue penetration, and significant tumor suppression.
- Importantly, D TBP-3 inhibited tumor growth and metastasis in an anti-PD-1 resistant tumor model.
Conclusions:
- D TBP-3 is the first d-peptide developed to target TIGIT.
- This novel therapeutic agent shows potential for overcoming resistance to current immunotherapies and offers a new strategy for cancer treatment.
More Related Videos
07:32Screening and Identification of Small Peptides Targeting Fibroblast Growth Factor Receptor2 using a Phage Display Peptide Library
Published on: September 30, 2019
09:06Development of a 68Gallium-Labeled D-Peptide PET Tracer for Imaging Programmed Death-Ligand 1 Expression
Published on: February 3, 2023
