Identification and assessment of peptides and single domain antibodies for cancer therapy
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Abstract
The discovery of immune checkpoint inhibitors has revolutionized cancer therapy. These immune checkpoint inhibitors suppress tumor growth by immune checkpoint blockade. This approach involves blocking inhibitory immune checkpoint pathways that are believed to play a crucial role in cancer progression. Immune checkpoint blockade has shown remarkable and enduring clinical responses across a broad spectrum of cancers. The most studied immune checkpoints are CTLA4, PD1, TIM3, BTLA, and LAG-3. Our first research work is focused on discovering peptide drugs to block the interaction of immune checkpoint protein TIM3 with its ligand Gal9, i.e., the TIM3/Gal9 pathway. Interaction of TIM3 with Gal9 inhibits immune cell functions and aids in tumor cells evasion from the immune system. Therefore, the goal of the research project is to block the interaction of TIM3/Gal9 pathway which helps to enhance the immune response against cancers. The cyclic peptide phage library was screened against TIM3 using a novel biopanning procedure. The peptides discovered were screened for their binding affinity and blocking efficiency. Unfortunately, no peptides were found to effectively bind to and block TIM3, prompting a discussion about the challenges in peptide drug discovery against the TIM3/Gal9 pathway. Similarly, the second project also aims to block the other immune checkpoint pathway i.e BTLA/HVEM pathway. First, we worked to develop peptides and then switched to single domain antibody (also known as nanobody or VHH) inhibitors that could bind to BTLA protein, thus preventing the binding of HVEM to BTLA helping to restore the immune response against cancers. We applied a novel biopanning technique to screen a sdAb phage library against BTLA and identified five promising candidates. Among them, sdAb Nb-E1, with a KD of approximately 312 nM and an IC₅₀ of about 616 nM, displayed significant binding affinity and blocking efficiency. It also demonstrated anti-tumor activity in a preliminary study on C57BL/6 mice bearing colon cancer. Another attractive approach for eliminating cancer cells is targeted therapy. This approach involves treating cancer by specifically targeting receptors overexpressed by tumor cells or molecules that are unique to a specific cancer type. Targeted therapy can be used to disrupt cancer cell proliferation or metastasis, thus offering therapeutic advantages in the treatment of various types of cancers. As CD44 isoforms are widely expressed in a wide range of cancers, targeting CD44 for targeted cancer therapy stands out as a promising approach in the development of novel therapeutics. Therefore, our goal is to discover CD44 binding peptide so that it can be conjugated with other therapeutic agents for targeted therapy. CD44-targeting cyclic peptides were identified through biopanning. The obtained peptides were screened for their binding activity towards CD44. Some peptides showed binding affinity to CD44. Moving forward, additional experiments should be conducted to further confirm the binding affinity of these newly discovered peptides.
Table of Contents
Introduction -- Literature review -- Identification of novel peptide to block TIM3/Gal9 pathway -- Identification of novel peptide and single domain antibody to block HVEM/BTLA pathway -- Discovery and evaluation of cyclic peptide ligands for targeting CD44 for the treatment of cancers -- Summary and conclusions
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Ph.D. (Doctor of Philosophy)