PeptiGrowth, a joint venture between PeptiDream and Mitsubishi Corporation, is focused on the invention of innovative peptide compounds for use in cell culture media.

Based in Tokyo, PeptiGrowth was created in 2020 to address challenges in regenerative medicine and cell therapy research, particularly the issues surrounding the use of recombinant protein growth factors, such as inconsistent quality, poor stability, high cost, and potential contamination with biological impurities.

PeptiGrowth utilizes PeptiDream’s patented Peptide Discovery Platform System (PDPS) to identify the best peptides which function as growth factors. According to the company, its synthetic peptide growth factors, also called “PG-peptides,” are produced entirely by chemical synthesis with improved and consistent quality and no risk of biological contaminants. To date, PeptiGrowth has released six products and have more in the pipeline.

Contract Pharma recently interviewed PeptiGrowth’s President and CEO, Jiro Sugimoto, who discussed the company’s background and plans for the future, as well as broader trends driving growth in regenerative medicine and cell therapy.

Contract Pharma: What are some of the trends driving the explosive growth in regenerative medicine and cell therapy?

Jiro Sugimoto: A big paradigm shift has been happening in the modality of pharmaceutical products over the decades. Conventionally, chemically synthesized small-molecule compounds were mainly used as active ingredients, but protein-based biopharmaceuticals, including antibodies, have been getting more and more popular recently.

However, even the advances of those protein-based biopharmaceuticals cannot fully meet the needs of treating various chronic diseases or rare diseases. Regenerative medicine and cell therapy products are aiming to literally regenerate and even strengthen the functions of organs, tissues, and cells to overcome such challenges. Recent advances in technologies to culture, isolate, and manipulate different cell types has made it possible to commercialize these therapies. Additionally, regulatory agencies have been devising regulations about efficacy and safety of these new therapies to support their growth and commercialization.

CP: What role do growth factors play in the regenerative medicine and cell therapy R&D and manufacturing process?

Sugimoto: Regenerative medicine and cell therapy products are manufactured by cell culture, often involving differentiation and proliferation of stem cells. Growth factors play an important role in cell culture, specifically in proliferation and differentiation of cells into final products. Cells present numerous kinds of receptors on their cellular membrane, and growth factors trigger cellular signaling events by binding to those receptors.

Although growth factors are not active pharmaceutical ingredients (APIs), and used only as media supplement, they are certainly critical components when manufacturing cell therapy and regenerative medicine products. There are also various small kinase inhibitors used to control cell fates; however, most of them are antagonists and cannot substitute growth factors whose agonistic activity is important. Our PG-peptides are designed to function equivalently to conventional growth factors, both as agonists and antagonists. Ideally, PG-peptides can technically substitute all the growth factors required in regenerative medicine and cell therapy fields.

CP: Why does the “traditional” production of protein growth factors present challenges to the pharmaceutical industry?

Sugimoto: Most traditional protein growth factors are made by fermentation technology, and they are usually very unstable and easily denature. Some products may also contain animal-derived components, which can also be an issue in the production of regenerative medicine and cell therapy products. Additionally, growth factors are generally purified from crude samples, such as cell extracts, which contain various kinds of proteins and even endotoxins in case of using E. coli for production. Consequently, the downstream purification processes are complicated and require intensive efforts to ensure product quality, which tends to reduce the yields of growth factors.

Furthermore, scaling up such tank-based fermentation requires intensive efforts to optimize culture conditions of cells or microorganisms, and often the production efficiency does not directly correlate with the size of fermenters. For these reasons, conventional growth factors have issues of lot-to-lot activity variations, potential contamination with biological impurities, limited scalability, and significantly high production cost. One of the important goals in the industry is to greatly reduce the cost of cell therapy and regenerative medicine products but the cost of growth factors accounts for a significant portion of the production cost.

CP: What is PeptiGrowth’s solution to these challenges?

Sugimoto: PeptiGrowth is developing synthetic peptides that have the equivalent functions to traditional protein growth factors, using PeptiDream’s proprietary technology, PDPS. These peptides are developed through screening a huge peptide library that can bind to the target molecules—typically receptor proteins of growth factors—and then selecting the peptides that work as either agonist or antagonist for the target molecules. Finally, the peptide sequences, linker type, length, and connecting position are optimized to fulfill the required properties such as EC50, Emax, solubility, and stability in medium. Our PG-peptides are not a mimetic form of conventional growth factors but rather designed to mimic their function with unique amino acid sequences. By providing these new functional peptides, we aim to overcome the challenges associated with conventional growth factors.

CP: What are the benefits of using alternative peptides in regenerative medicine and cell therapy R&D and manufacturing?

Sugimoto: PG-peptides are chemically synthesized and completely animal-component-free. Because of the nature of chemical synthesis, we can ensure high purity and consistent quality, enabling reproducible results in the production of regenerative medicine and cell therapy products. Additionally, PG-peptides are highly scalable and can provide a significant cost advantage over conventional growth factors.

CP: What are the challenges of using alternative peptides?

Sugimoto: The challenges of using our PG-peptides might arise from their “novelty” and people may have concerns about using such novel products. With that being said, we conducted off-target panel assays against 68 different targets and cytotoxicity assays using human-derived cells in the development process of our PG-peptides. We confirmed in these assays that all the peptides we have launched up to now (PG-001~PG-006) have almost no off-target activity or cytotoxicity, even at micromolar concentration ranges, which are more than 1,000 times higher than the concentration PG-peptides are usually used at. These data support the specificity and safety of our PG-peptides.

Additionally, since all our PG-peptides do not have membrane permeability, we assume that most of them can be washed out by media exchange during the production of cellular products. However, to further ensure safety of PG-peptides, we are planning to quantify residual concentrations inside cells and conduct in vivo cytotoxicity assays at the maximum concentration possible. We will provide such additional data once available.

CP: What are some recent company highlights?

Sugimoto: In the past 12 months, we have launched three products:

• PG-004: Noggin-like peptide (BMP4/7 family inhibitor)
• PG-005: BMP7 selective inhibitor
• PG-006: BMP4 selective inhibitor

PG-004 can be utilized for the development of various types of organoids, including kidney, intestine, and lung. PG-005 and 006 are unique peptides that enable selective inhibition of BMP7 and BMP4 families, which is not possible with conventional recombinant Noggin or small kinase inhibitors. We expect that those PG-005 and 006 can be utilized to gain deeper understanding of BMP signaling as well as development of novel cell differentiation processes.

In addition, we have obtained feedback from a lot of customers who have tested our PG-peptides, and most of them turned out to be positive. We have also created application notes in collaboration with a Japanese start-up company named Jiksak Bioengineering Inc. Jiksak Bioengineering conducted an experiment generating neuron axon bundles by utilizing their iPSC-derived Nerve Organoid system to evaluate the activities of recombinant BDNF (brain-derived neurotrophic factor) and our PG-003: BDNF alternative peptide. The quantitative analysis revealed that even longer and thicker axon bundles were formed with our PG-003 than recombinant BDNF. These data support that PG-003 has equivalent activity to BDNF not only in basic cell signaling activation but also in high-level phenotype of neuron cells.

With all the activities in the past 12 months, we are confident that our PG-peptides can surely substitute conventional growth factors and that we can bring significant benefit to the entire regenerative medicine and cell therapy industries.

CP: What are PeptiGrowth’s plans for future expansion？

Sugimoto: We are currently developing peptides for different types of growth factors. We expect that alternative peptides for major growth factors such as bFGF, EGF, VEGF, PDGF-AA, TPO, and Wnt3a will be launched in 2023 or early 2024. Following those factors, other important growth factors, such as TGF beta superfamily, Activin A, BMP4, TGF beta 1 as well as Interleukin series, are in our development pipelines. Once we complete the development of these peptides, we can cover most of the growth factors commonly used in regenerative medicine and cell therapy fields.

In addition, we are now looking for collaboration opportunities to develop cell culture media using our PG-peptides. During the marketing activities, we have learned that many researchers are using specialized media kits that contain a mixture of growth factors to culture specific types of cells. We believe that such easy-to-use products are well received by researchers and that the development of such media is essential to expand the market for our PG-peptides. Since our PG-peptides are more thermostable than conventional growth factors, we believe that we can even add PG-peptides in media to make it a completely ready-to-use product, which we believe is a great benefit that we can potentially provide to our customers.

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