Accelerated immunotherapeutic development through improved transmembrane protein manufacturing

Proteins are an essential component of life. The scientific journey into the exploration of proteins only started in 1789, when the first protein, albumin, was first discovered. Amino acids, the building blocks of proteins, were found 20 years later. However, after 200 years of scientific discovery, the question still remains as to whether researchers truly understand proteins and their complexities.

It is reasonable to assume that researchers do not know everything; however, throughout the course of many years of scientific discovery, proteins have evolved into an essential component of healthcare as drug targets, medicines, and diagnostic assays.

Proteins are essential to the healthy function of the human body. They are driven by their roles as effector molecules that are created directly from our genes, meaning that it is vital to understand and utilize these macromolecules. Transmembrane proteins have shown to be an especially tricky class of proteins to understand and use in medicine in recent years.

Dr. Carrie Qin, associate director of product R&D and transmembrane protein expert at ACROBiosystems, explains the challenges of transmembrane protein research and how its proprietary FLAG technology can help when it comes to the development of drugs.

Accelerated immunotherapeutic development through improved transmembrane protein manufacturing

Image Credit: ACROBiosystems

What are transmembrane proteins, and why are they important to research?

Transmembrane proteins are large macromolecules that are embedded into the cell surface. An easier way to understand the cell surface is to think of it as the surface of the earth but on a much smaller scale. Random assortments of carbohydrates, lipids, and other proteins stain the surface of the cell, just as mountains, trenches, and trees stain the surface of the earth.

Transmembrane proteins, in this metaphor, are much like volcanoes that link the deep molten core to the atmosphere. On the cellular level, however, transmembrane proteins will serve as a vital link between the intracellular and extracellular environments. These proteins let numerous ions and molecules enter and exit the cell in addition to relaying activation or responding to extracellular stimuli.

Most of these external stimuli will then propagate intracellularly via internal signaling pathways, resulting in the regulation of cell metabolism, cellular fate and cellular activity.

How does the role of transmembrane proteins in the signaling pathway translate to its potential as an immunotherapeutic target?

Transmembrane proteins, in general, serve as the gatekeeper of the cell, allowing certain signals through while blocking others. Diseases are commonly connected with improperly functioning transmembrane proteins, which result in discordant cellular signaling and, as a result, cell function.

The Claudin transmembrane protein family, for example, plays an important role in coordinating cellular activities and establishing tight junctions between cells.

Claudins are commonly upregulated and overexpressed in malignancies, resulting in aberrant activation of downstream pathways. In some cases, abnormal Claudin function will disrupt tight-junction function, resulting in cancer stem cell breaching, metastasis, migration, and tumor invasion.

As a result, drug therapies that inhibit transmembrane proteins, like the Claudin family, have enormous potential in the fight against cancer.

With transmembrane proteins such as Claudin showing promise as an immunotherapeutic target, what is limiting transmembrane protein research?

One of the major limiting factors in transmembrane protein research is the lack of a viable antigen that can be used in research. Unlike the production of traditional intra- or extracellular proteins, the production of transmembrane proteins for research purposes is an extremely complex and challenging process. This is a substantial impediment to the development of an immunotherapeutic target's associated drug therapy.

There are three major challenges: low expression levels, low abundance, and aggregation. The size of transmembrane proteins causes low expression levels. Transmembrane proteins are significantly constrained by the available surface area of a cell because they are huge, surface-bound macromolecules.

Moreover, as these proteins act as signaling gatekeepers, their overexpression is likely to result in cytotoxicity.

Furthermore, because transmembrane proteins are often hydrophobic, they can agglomerate and undergo conformational changes in less-than-ideal conditions. Overall, it is a huge difficulty to scale up and produce high purity, high quality, and viable transmembrane proteins for research use.

What is FLAG, and how does it overcome the challenges in current transmembrane protein manufacturing?

FLAG, which stands for Full-length Active Gallery, is a technology platform designed to directly address manufacturing difficulties. To maximize the number of full-length, multi-pass transmembrane proteins, ACROBiosystems redesigned the complete development system and adjusted the expression interval, expression system, and culture conditions.

They also built a strict quality control system that included dynamic light scattering evaluations to monitor structural homogeneity. Generating transmembrane proteins is also only half the solution.

ACROBiosystems also created three platforms for delivering transmembrane proteins to customers: virus-like particles, detergent micelles, and Nanodiscs. Each provides distinct advantages for various applications like quantitation, drug screening, and affinity verification.

The term “Full-length” seems to be a big emphasis point for FLAG. Please can you explain why this is an important factor in drug development?

Due to the difficulties in the creation and expression of entire transmembrane proteins, drug research is usually carried out using shortened or a portion of the transmembrane protein, mostly the target area for interaction.

The extracellular domain (ECD) is the principal component of the transmembrane protein that is replicated and utilized. However, this only provides a partial picture of the drug-transmembrane protein interaction.

Rituximab (RTX) and CD20 are two famous examples. As CD20 contains two ECDs, CD20-targeting therapies like RTX may attach to both extracellular loops. A comprehensive examination of complement-dependent cytotoxicity and mechanism of action analysis is difficult without the expression of both ECDs, thus stressing the importance of using full-length transmembrane proteins as antigens.

ACROBiosystems has been able to give its customers native, “full-length” transmembrane proteins for use in research and drug therapy studies, thanks to its FLAG technology.

Beyond research and development, how does ACROBiosystems contribute to immunotherapy manufacturing?

Drug development is a lengthy and exploratory process with numerous uncertainties. As ACROBiosystems manufactures critical reagents for breakthrough drugs and therapies, quality is one of the top concerns in all of its products.

ACROBiosystems has built strong quality management systems that are certified and audited in accordance with ISO 9001:2015 and ISO13485:2016 norms. It is able to systematically standardize the whole production process for its products, which include recombinant proteins, antibodies, enzymes, cell culture cytokines, assay kits, and many others, using this approach.

About ACROBiosystems

ACROBiosystems is a cornerstone enterprise of the pharmaceutical and biotechnology industries. Their mission is to help overcome challenges with innovative tools and solutions from discovery to the clinic. They supply life science tools designed to be used in discovery research and scalable to the clinical phase and beyond. By consistently adapting to new regulatory challenges and guidelines, ACROBiosystems delivers solutions, whether it comes through recombinant proteins, antibodies, assay kits, GMP-grade reagents, or custom services. ACROBiosystems empower scientists and engineers dedicated towards innovation to simplify and accelerate the development of new, better, and more affordable medicine.

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Last updated: Jul 9, 2024 at 7:45 AM


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