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A barrier-crossing and immune checkpoint-blocking antibody fusion protein for enhanced glioma-targeted immunotherapy
Yanning Bao1, Shengmin Yang1, Yuan Ding1
1Department of Pharmaceutics, School of Pharmaceutical Sciences, Fudan University & State Key Laboratory of Advanced Drug Formulations for Overcoming Delivery Barriers, Shanghai 201203, China.
Abstract:
With low five-year survival estimates, poor prognosis, and high recurrence probabilities, glioma is considered one of the most intractable malignant tumors. Despite the discovery of lymphatic vascular system and immune system in the central nervous system (CNS), immune checkpoint blockade therapeutics, such as programmed death ligand 1 (PDL1, also called B7H1 or CD274) antibodies, are prevented from the CNS and glioma sites due to the existence of biological barriers including the blood-brain barrier (BBB) and blood-brain tumor barrier (BBTB). Herein, we constructed a BBB/BBTB-crossing recombinant antibody by fusing the PDL1 antibody (αPDL1) and the targeting moiety RAP22 peptide (RAP22) through a matrix metalloproteinase 2 (MMP2)-responsive cleavable linker, abbreviated as αPDL1-mRAP22. Not only was αPDL1-mRAP22 able to block PD1/PDL1 pathway, reduce T cell apoptosis, enhance T cell killing ability towards glioma cells in vitro, but also it showed higher accumulation in the glioma site, prolonged survival time, and potent immune responses as well as synergistic effects with temozolomide (TMZ) in vivo, offering a novel strategy for glioma immunotherapy.
Insights
A novel recombinant antibody, αPDL1-mRAP22, crosses the blood-brain barrier to enhance glioma immunotherapy. This approach targets programmed death ligand 1 (PDL1) and shows promise in preclinical models.
Area of Science:
- Neuro-oncology
- Immunotherapy
- Biotechnology
Background:
- Glioma is a challenging brain tumor with poor survival rates.
- Biological barriers like the blood-brain barrier (BBB) limit CNS drug delivery.
- Immune checkpoint inhibitors face challenges entering the central nervous system (CNS).
Purpose of the Study:
- To develop a BBB/BBTB-crossing antibody for glioma immunotherapy.
- To overcome limitations of current immune checkpoint blockade in the CNS.
- To create a novel therapeutic strategy for intractable brain tumors.
Main Methods:
- Constructed a recombinant antibody (αPDL1-mRAP22) fusing a PDL1 antibody and RAP22 peptide via an MMP2-cleavable linker.
- Evaluated the antibody's ability to block PD1/PDL1 pathway and affect T cells in vitro.
- Assessed in vivo efficacy, including BBB/BBTB penetration, immune response, and survival.
Main Results:
- αPDL1-mRAP22 successfully crossed the BBB/BBTB.
- The antibody blocked PD1/PDL1, reduced T cell apoptosis, and enhanced T cell killing of glioma cells.
- In vivo studies showed enhanced glioma site accumulation, prolonged survival, potent immune responses, and synergy with temozolomide (TMZ).
Conclusions:
- αPDL1-mRAP22 represents a novel strategy for glioma immunotherapy by overcoming CNS barriers.
- This engineered antibody demonstrates potential for treating aggressive brain tumors.
- Further research into this BBB-penetrating immunotherapy holds promise for improved patient outcomes.
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