Designed Mechanistically Rational Stabilized Peptide-based Immuno-combination Therapy for Managing Metastatic Breast Cancer

Tripathi, Archana (2026) Designed Mechanistically Rational Stabilized Peptide-based Immuno-combination Therapy for Managing Metastatic Breast Cancer. PhD thesis, Indian Institute of Science Education and Research Kolkata.

Text (PhD thesis of Archana Tripathi (18RS088)) 18RS088.pdf - Submitted Version Restricted to Repository staff only Download (15MB)

Abstract

The key aim of this work is to develop mechanistically rational stabilized peptide-based immuno-combination therapy for managing metastatic breast cancer. Breast cancer is the most common form of malignancy and mortality among women. It is also the second most prevalent form of cancer worldwide. Current therapeutic approaches like surgery, radiation therapy, chemotherapy endocrine therapy etc fail to completely cure the advanced form of breast cancer and distant organ metastases. Recently, antibody-based cancer immunotherapy has emerged as a highly promising approach for cancer treatment. However, the successful implementation of this therapy faces significant challenges due to its high cost, the proteolytic instability of antibodies, and adverse immune responses due to non-specific activation of the entire immune system. Cancer cells express the “cluster of differentiation 47” (CD47) protein, an "eat me not" signal, which interacts with the “signal regulatory protein alpha” (SIRPα) receptor on macrophages, thereby evading immune surveillance by preventing phagocytosis. The CD47-SIRPα cross-talk inhibits phagocytosis in macrophages. To address these challenges, we have employed a rational hybrid peptide design strategy to engineer cost-effective, protease-stable, improved peptide-based therapeutics aimed to disrupt the CD47-SIRPα signaling axis. Additionally, Nuclear Factor κB (NF-κB) signaling is upregulated in highly metastatic triple-negative breast cancer, promoting tumor cell proliferation, metastasis, and upregulation of CD47. We have developed an improved immuno-combination therapy that includes both a CD47-SIRPα axis blocker and an NF-κB inhibitor to enhance the therapeutic efficacy. Chapter 1 provides a brief description about the emergence of cancer immunotherapy with a special emphasis on peptide-based immunotherapeutics against TNBC. In Chapter 2, we have developed peptide-based CD47 inhibitor and immuno-combination therapy having peptide-based CD47 and NF-κB inhibitor. In Chapter 3, we have developed bispecific peptide-based inhibitor of CD47 and SIRPα. Our experimental data described in both the chapters infer that our peptide-based immunotherapy and immuno-combination therapy has significant translational potential and such strategy will strengthen the drug development initiative of “Self-reliant” India.

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