Protein Folding Chaperone BiP As Molecular Target For Immunotherapy

Release Date: 24-Feb-2023

Protein folding is an important event in making a polypeptide chain functional for biological use. The biologically active version of the protein is in its native 3D shape, which is attained with the aid of many chaperone proteins. In recent years, as the quest for creating effective cancer therapies made progress, these chaperone proteins have come into focus as potential targets for drug development for immunotherapy. BiPS or GRP-78 is one such protein that helps in protein folding and translocation of the protein. BiPS is shown to be elevated in many malignancies, indicating that it may have more functions than are now understood, particularly in cancer. Therefore, because of the myriad of roles BiPS plays in cancer survival and proliferation has helped emerge as a promising target for cancer treatment.


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Binding immunoglobulin protein, or BiP, has low expression under levels under normal expression but is overexpressed in cancers like breast cancer and pancreatic cancer. In relation to its pro-cancer roles, BiP has been demonstrated to connect with Stathmin1 (STMN1) to drive tumor metastasis in relation to its pro-cancer effects. Moreover, its overexpression encourages the expression of matrix metalloproteinases, which are crucial to various stages of the development of malignant tumors. It is also a direct regulator of stress-release proteins, which aids in the survival of cancer cells. In an unfolded protein response, BiP binds to unfolded proteins, correcting their folding. In this process, it simultaneously also triggers physiological reactions that reduce protein synthesis after a series of phosphorylation by the PERK, IRE1, and ATF6 signaling pathways. Additionally  the protein also imparts resistance to cancer therapy. As a result, the protein either directly or indirectly contributes to the survival of cancer cells through a variety of pathways.


Many research studies have been conducted in recent years to emphasize its potential as a therapeutic target, and the outcomes have been encouraging. It was discovered that the deletion of BiP decreased the expression of matrix metalloproteinases and blocked the RhoA signaling pathway, preventing tumor invasion. Thus, it has been proposed that the knockout of BiP will lessen cancer cell invasion, which will lessen cancer cell proliferation, migration, colony formation, and other activities.


The BiP protein has clear potential as a therapeutic target, but the dearth of clinical trials and medications in the early stages of development underline the protein's current lackluster interest. Drugs that target immunological checkpoint proteins predominate in the clinical development of immunotherapy. However, the need for identification of new protein targets will be highlighted by the overabundance of these drugs in the pipeline and the escalating market competition. The BiP protein has a lot of potential in this regard because of the variety of roles it performs in the body.


BiPER Therapeutics was among the first companies that started targeting the protein BiP. With its candidate BPR001, a first-in-class small molecule inhibitor that targets the protein, the company has been a pioneer in BiP targeting. The candidate has a unique and targeted mechanism that it uses to destroy cancer cells specifically. By focusing on this pathway, BPR001 is able to overcome this survival mechanism and this resistance, improving outcomes in both sensitive and resistant cancers. Cancer cells express permanent and high ER Stress levels in order to survive, proliferate, and become resistant to standard of care therapies. In both monotherapy and in combination with other anti-cancer medications, BPR001 has already shown outstanding outcomes across a wide range of indications.


In February 2023, the company received EUR 1.25 million (US$ 1.33 million) in seed capital. BiPER will be able to work over the next 15 months on the preclinical development of BPR001 for the treatment of gastrointestinal cancers and advance it to the clinical trial application (CTA)/investigational new drug (IND) phases. The company also intends to use this investment to advance its other candidate, which eliminates cancer cells by causing stress.


Drug research aimed at the BiP protein is still in its early stages. BiP, however, has a lot of promise for its involvement in cancer, which is not restricted to any specific cancer, demonstrating in the possibility of its applicability in a range of malignancies. This is because researchers are exploring for other alternative proteins to employ as targets for drug development. Drugs that target novel targets are desperately needed, and a number of market drivers are promoting the expansion of this market sector. The market for BiP-targeting medications is anticipated to expand rapidly in the years to come as significant investments flow in.

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