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Your Position: Home > Insights > Multi-pass Transmembrane Proteins Facilitate Targeted Drug Development
Multi-pass Transmembrane Proteins Facilitate Targeted Drug Development
Release time: 2025-01-17 Source: ACROBiosystems Read: 287

Multi-pass Transmembrane Proteins Facilitate Targeted Drug Development

Global Drug Pipeline Thriving, Strong Innovative Drug Research Market

In recent years, the innovative drug market has rapidly grown, with predictions of strong growth continuing to 2031. Innovative drug research and development (R&D) now shows unprecedented vitality and potential, fueled by policy incentives and capital market support. Many pharmaceutical companies are actively investing in this area, competing fiercely to seize market share. With patient populations expanding and market demand growing, differentiated R&D pipelines and precise targeting are crucial for companies to distinguish themselves.

Multi-pass Transmembrane Proteins Facilitate Targeted Drug Development

Data Source: Market Research Intellect

Multi-pass Transmembrane Proteins: A Focal Point in Innovative Drug R&D

Transmembrane proteins (TPs), also known as integral membrane proteins, constitute 70% to 80% of the total TPs and represent the primary drug targets at this stage, accounting for over 60% of all targets, particularly exceeding 90% in the case of antibody drug targets. Among them, the structurally complex multi-pass TPs (such as GPCRs, ion channels, and transporter proteins) play crucial roles in material transport and signal transduction and are closely associated with various diseases, including the pathological processes of major diseases like neurodegenerative diseases, autoimmune diseases, developmental disorders, and malignancies. Currently, numerous targeted research projects focusing on multi-pass TPs are actively being conducted worldwide, which hold promise for providing more targeted therapeutic options in the future.

Overview: Multi-pass TPs as Prevalent Targets for Cutting-edge Drug R&D

CD20: Popular Target in Bispecific Antibody Field

CD20 is a four-pass TP primarily expressed on the surface of B lymphocytes. As an important marker for B-cell lymphomas, CD20 has become a crucial target for various anti-lymphoma drugs. However, CD20's application is not limited to monoclonal antibody therapies. By combining with the CD3 target, the development of bispecific antibodies (bsAbs) has enabled the recruitment of T cells to the vicinity of B cells, thereby enabling T cells to kill B cells. As a currently popular target combination, CD3/CD20 bsAbs are not only favored in the field of hematological malignancies but also provide a new treatment option for refractory or relapsed non-hodgkin's lymphoma (NHL), multiple myeloma (MM), and other areas where drug resistance is an issue.

Multi-pass Transmembrane Proteins Facilitate Targeted Drug Development

Diagram of CD20 Structure

Claudin 18.2: A New Hope for Gastric Cancer Treatment

Claudin 18.2 belongs to the Claudins family and is a four-pass TPs. Unlike Claudin 18.1, which is primarily expressed in normal lung tissue, Claudin 18.2 is specifically expressed in differentiated gastric mucosal epithelial cells but not in gastric stem cell areas. This difference allows therapeutic antibodies targeting Claudin 18.2 to have greater anticancer potential and lower toxicity in the treatment of gastric cancer. On October 18, 2024, the United States Food and Drug Administration (FDA) approved Zolbetuximab, the first monoclonal antibody targeting Claudin 18.2, for use in combination with chemotherapy to treat Claudin 18.2-positive, unresectable, advanced, or recurrent gastric cancer or gastroesophageal junction adenocarcinoma. This approval provides the first and only targeted treatment option for patients with Claudin 18.2-positive gastric cancer.

Multi-pass Transmembrane Proteins Facilitate Targeted Drug Development

Diagram of Claudin 18.2 Structure

GPRC5D: An Ideal Target for Multiple Myeloma

GPRC5D is a seven-pass TP and a key member of the G protein-coupled receptors (GPCRs). It is highly expressed in malignant plasma cells, but is limited to hair follicle regions in normal tissues, demonstrating a high degree of specificity. Given this characteristic, GPRC5D is considered an ideal target for designing immunotherapy strategies for multiple myeloma. Currently, several immunotherapeutic approaches targeting GPRC5D are under development, including T-cell redirecting bsAbs and CAR-T therapies. As an emerging drug target, GPRC5D may bring hope for exploring new breakthroughs in the treatment of multiple myeloma.

Multi-pass Transmembrane Proteins Facilitate Targeted Drug Development

Diagram of GPCRs Structure

Claudin 6: A Potential Target for Solid Tumors

Claudin 6 is a member of the Claudins family. Studies have found that Claudin 6 is highly and specifically expressed in various solid tumor tissues, including ovarian cancer, testicular cancer, endometrial cancer, gastric cancer, liver cancer, and non-small cell lung cancer, and its expression is negatively correlated with prognosis. However, it is almost absent in normal adult tissues. Based on its strict silence in healthy adult tissues but abnormal activation and high-level expression in various solid tumors with high medical needs, Claudin 6 is thriving in multiple drug research fields and has been regarded as one of the ideal targets for anticancer therapy in the Claudin family, following Claudin 18.2.

Multi-pass Transmembrane Proteins Facilitate Targeted Drug Development

Diagram of Claudin 6 Structure

STEAP1: A Potential Target for Tumor Immunology

STEAP1 is a six-pass TP primarily expressed on the surfaces of tumor cells and immune cells. Studies have shown that STEAP1 is highly expressed in various tumors and is closely related to the malignancy and prognosis of tumors. Furthermore, STEAP1 is involved in iron metabolism and plays a crucial role in the growth and proliferation of tumor cells. Therefore, STEAP1 has emerged as a new target for tumor immunotherapy. Antibody drugs and CAR-T cell therapies targeting STEAP1 are currently under development, offering potential new strategies for tumor treatment.

Multi-pass Transmembrane Proteins Facilitate Targeted Drug Development

Diagram of STEAP1 Structure

CCR8: A Key Target for Tumor Immunology

CCR8 is a seven-pass GPCR that is highly and specifically expressed on tumor-infiltrating tregs, with very low expression in peripheral blood and normal tissues. Targeting CCR8 allows for precise modulation of the immunosuppressive state within the tumor microenvironment. Studies have shown that the combination of CCR8-targeted drugs with PD-1 inhibitors significantly enhances antitumor activity, suggesting that CCR8 has the potential to become the next major target in the field of tumor immunosuppression, following PD-1.

Multi-pass Transmembrane Proteins Facilitate Targeted Drug Development

Diagram of CCR8 Structure

Full Length Active Gallery: Comprehensive Solutions to Overcome Research Challenges in Preparing Multi-pass TPs

Despite playing a central role in a wide range of physiological and pathological processes and being closely associated with various diseases, the research path for multi-pass TPs is fraught with challenges. Such as the high structural complexity of multi-pass TPs makes it extremely difficult to obtain full-length protein samples that maintain their native conformation through traditional means; coupled with their low expression levels, purification processes are hindered by their hydrophobic properties and structural complexity, making it difficult to produce high-purity, high-activity target proteins; in addition, functional validation highly depends on specific experimental conditions and sophisticated techniques. These factors have severely hindered the progress in the development of drugs targeting multi-pass TPs.

ACROBiosystems has specifically established a more comprehensive platform-based solution for the research and production of multi-pass TPs – Full Length Active Gallery – with stabilized structure and high activity to facilitate drug development and mechanism studies.

•  Higher abundance than that of overexpressing cells

•  Can be used as the optimal targets for dendritic cells and phage display in vivo because of their 100-300nm in size

•  Suitable for immunization / ELISA / SPR / BLI / cell experiment / CAR detection

•  Multi-pass TPs with complete conformation

•  Can be accurately quantified

•  Suitable for immunization / ELISA / SPR / BLI

•  Full-length multi-pass TPs are in a natural membrane environment retaining high biological activity

•  High hydrophilicity without detergents

•  Suitable for immunization / ELISA / SPR / BLI / cell experiment / CAR detection

Hot Molecules in Full Length Active Gallery


We also provide corresponding stable cell line products and cell line development service to facilitate drug development and clinical submission. Welcome to inquiry~

Reference

1. Thomas, Benjamin, Karuppiah Chockalingam, and Zhilei Chen. "Methods for Engineering Binders to Multi-Pass Membrane Proteins." Bioengineering 10.12 (2023): 1351.

2. Chen, **xia, et al. "Targeting CLDN18. 2 in cancers of the gastrointestinal tract: New drugs and new indications." Frontiers in Oncology 13 (2023): 1132319.

3. Xu, Michael, et al. "STEAP1–4 (six-transmembrane epithelial antigen of the prostate 1–4) and their clinical implications for prostate cancer." Cancers 14.16 (2022): 4034.

4. Bar-Or, Amit, et al. "Clinical perspectives on the molecular and pharmacological attributes of anti-CD20 therapies for multiple sclerosis." CNS drugs 35.9 (2021): 985-997.

5. Berenguer, Jordi, et al. "Glycosylated extracellular vesicles released by glioblastoma cells are decorated by CCL18 allowing for cellular uptake via chemokine receptor CCR8." Journal of extracellular vesicles 7.1 (2018): 1446660.

6. https://atlasgeneticsoncology.org/gene/50974/cldn6-%28claudin-6%29.

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