Summary
- Closed for EoI
- Profile Type
- Research & Development Request
- POD Reference
- RDRTR20240701017
- Term of Validity
- 1 July 2024 - 1 July 2025
- Company's Country
- Turkey
- Type of partnership
- Research and development cooperation agreement
- Targeted Countries
- All countries
Contact the EEN partner nearest to you for more information.
Find my local partner
General information
- Short Summary
- The GX-G3 project aims to market a 3rd generation treatment for chemotherapy-induced neutropenia, improving upon Filgrastim and Pegfilgrastim. Utilizing Genexine’s hybrid-Fc (hyFc) platform, GX-G3 enhances blood circulation and reduces immunogenicity by combining human IgD-Fc and IgG4-Fc, which prevents ADCC and CDC reactions.
- Full Description
-
The aim of the project is to have GX-G3 product in the market as 3rd generation candidate for the treatment of chemotherapy-dependent neutropenia. Neutropenia increases the mortality risk either in short-term due to inflammations or in long-term due to insufficient chemotherapy. To recover neutropenia developed after chemotherapy, national and international authorities propose the usage of G-CSF. GX-G3 developed as an alternative, 3rd generation treatment to Filgrastim (1st generation) and Pegfilgrastim (2nd generation). GX-G3 is designed as hybrid-Fc (hyFc) platform by aiming long-acting and enhanced blood circulation by eliminating antibody-dependent (ADCC) and/or complement-dependent (CDC) cellular toxicity.
Fc-fusion technology provides an opportunity to increase half-life of proteins but with potential presence of undesired immune responses. The Fc domain of Ig has also effector functions such as antibody dependent cell-mediated cytotoxicity (ADCC) or complement-dependent toxicity (CDC). This effector functions are generally achieved via interaction between Fc region of the Ig and Fc receptors on effector cells or via complement binding. Therefore, the blocking of effector functions of Fc should be performed to reduce undesired reactions such as cell killing, interleukin release or inflammation. The proprietary Hybrid Fc platform has been invented both to further improve plasma half-life of conjugated drugs and reduce ADD and CDC. For this purpose, two different IgGs, Ig4 and IgD, having no ADDC and CDC response combined. The Hybrid Fc is effective, when joined to a biologically active molecule, to increase half-life of the biologically active molecule.
hyFc is Genexine’s innovative platform technology to construct a long-acting and safe Fc fusion protein. Unlike previously developed Fc products, human Fc used in GX-G3 is in a hybridized form of human IgD-Fc and IgG4-Fc, named hybrid Fc.
In general, Fc of an antibody binds to FcRn (neonatal Fc receptor) of endothelial cells in the human body, thereby enabling the recycle of hyFc-fused proteins resulting in a product with markedly longer half-life. Similar to other Fc fusion agents, it is expected that GX-G3 could have a long-acting characteristic in serum because of its FcRn binding affinity and decreasing renal clearance. Hinge-CH2 domain of IgD in hyFc construct has significant hinge flexibility but no binding affinity with FcγR inducing antibody-dependent cellular cytotoxicity (ADCC) while CH2-CH3 domain of IgG in hyFc does not exhibit any complement-dependent cellular cytotoxicity (CDC) reaction. Inherent human G-CSF amino acid sequence without the introduction of any mutation is used in the hyFc platform and lgD/lgG4 fused junction site of hyFc is buried in an unexposed region, thereby minimizing immunogenicity. Consequently, as might be expected, GX-G3 exhibits long-acting characteristic as well as lower immunogenicity without ADCC and CDC reactions. In contrast to Pegfilgrastim, GX-G3 is prepared by inserting G-CSF-hyFc expressing gene in eukaryotic expression vector of pAD15 into MCS (multicloning site) and is obtained without any conjugation step. Streamlined purification process of hyFc-fusion proteins eliminates longer steps in the biological purification process of Pegfilgrastim, resulting cost-effective manufacturing.
With respect to its structure and characteristic features, hyFc fused G-CSF is unique regarding a longer plasma half-life, efficient expression level, eliminated cytotoxicity and reduced immunogenicity, opening a road to be the next generation G-CSF with many therapeutic applications.
To produce GX-G3 as G-CSF agents, Chinese Hamster Ovary (CHO) cells are used as host cell which is different than other G-CSF agents. Instead of producing G-CSF and Fc-antibody separately and integrating them via chemical reactions, single production step is utilized by G-CSF-hyFc fusion. By these advance properties, GX-G3 stability and the cost of production - Advantages and Innovations
-
1)Improved Efficacy
2)1 injection/chemo cycle
3)Faster than 1st and 2nd generation G-CSF drugs in terms of neutrophil recovery
4)Long-Acting
5)Longer half-life thanks to proprietary hybrid immunoglobulin platform hyFc.
6)Lower Cost
7)Cost competitive manufacturing thanks to the simplified
8)Improved Safety
9)No antibody mediated (ADCC) and complementary dependent (CDC) cytotoxicity of hyFc
10)No vacuolation
11)Less side effects
12)Solid Intellectual Property
13)GX-G3 drug molecule is patented until 2028
14)GX-G3 product formulation and method of use patents are granted and patents will be valid till 2038 and 2039, respectively. - Technical Specification or Expertise Sought
-
1) Analytical Biosimilarity Assessments; 2) Licensing-out; 3) Cell Line and Process Development. These 3 parts are described as overall services and technologies that are covered in the center. In the first section, produced biotechnological products are analyzed based on ICHQ6B guideline. Identity, purity, and potency are the main characteristics covered to assess biosimilarities of the products. On the other hand, external products with specific privacy agreement are able to be analyzed and extensively reported. By this manner, these assessments cover size-exclusion chromatography (SEC), cation-exchange chromatography (CEX), reverse-phase chromatography (RP-HPLC), titer determination by Pro-A, and glycan profiling. Purity includes the analysis of the product based on intact mass, peptide mapping, disulfide bond determination, and post translational modifications while potency tests include efficacy, ADCC, and CDC activities' analysis. The other main assessment covers licensing-out services.
In the analytical process, in order to determine the chemical, biological and structural properties of the biosimilar product compared to the reference product; Western Blot to identify the molecular weight of the product based on its immunological properties, SDS-PAGE (Sodium dodecyl sulfate polyacrylamide gel electrophoresis) to qualitatively determine the molecular weight and aggregation/degradation level of the product, SEC-HPLC to quantitatively determine the aggregation/degradation level and monomeric purity. (Size Exclusion Chromatography), RP-UPLC (Reverse-phase Chromatography) to check various modification (deamidation, oxidation) and degradation products that may change the hydrophobic character of the product, HIC (Hydrophobic Interaction Chromatography), 280 nm to determine the hydrophobic purity of the protein without denaturing it. UV-visible spectroscopy to determine the molar absorptivity coefficient of the product, CEX-HPLC (Cation Exchange Chromatography) to determine the charge variant profile quantitatively at high resolution, ProteinA-HPLC to determine the amount of harvest products in a short analysis time, producing higher amounts of product with spare clones. Fc-ELISA to evaluate the clone efficiency, GX-G3 ELISA to determine the specific binding activity of the product to its antigen (G-CSF), Glycan to determine the N-glycans that play a role in the effectiveness of the product; Gel isoelectric focusing for the purpose of qualitative determination of the charge variant profile; In vitro bioactivity will be used to determine the biological activity of the product, ELISA will be used to determine receptor binding kinetics, FTIR (Fourier Transform Infrared Spectroscopy) analysis will be used to analyze the secondary structure, and Fluorescence Spectroscopy methods will be used to analyze the tertiary structure.
The drug's charge variants and glycan profile are the features that have the greatest impact on the drug's activity and stability. Therefore, it is critical to control it throughout the entire process. Additionally, amino acid sequence analysis (peptide mapping), analysis of post-translational modifications, analysis of disulfide bonds, Mass spectrometry for intact mass-glycoform analyses, Capillary Electrophoresis to determine the charge variant profile and aggregation/degradation level, antigen (G-CSF) that play a role in product activity. ) and SPR (Surface Plasmon Resonance) for Fc receptor binding kinetics analyses, 2D (two-dimensional) gel electrophoresis, particle size analyzes (LO - Light Obscurration) for both molecular and charge-based analysis of the protein and separation and characterization of host cell proteins coming from the process. and DLS - Dynamic Light Scattering Spectrometry), secondary structure determination analysis (CD - Circular Dichroism), melting temperature determination analysis (DSC - Differential Scanning Calorimetry) and biosimilarity comparison studies will be carried out. The product amino acid sequence is critical for analysis of modifications that determine product activity and half-life.
In particle size analysis, DLS is essential for the early detection of aggregation that may occur in the product. It is also widely used in stability studies. The LO method, which is included in the pharmacopoeia, is considered the 'gold standard' for particle counting. The CD method, which analyzes the secondary structure of the product, is of great importance for checking whether the protein is folded correctly at every stage of production. The DSC method, which is used to measure protein melting temperature, is an important criterion in determining the stability of the product in different formulations. In addition to the specified chemical and biological characterization analyses, HCD (Host cell DNA), HCP (Host Cell Protein), Leak Protein-A, ELISA, Endotoxin analyzes will also be applied to determine process-related impurities. Additionally, antigen-dependent cell cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) are the two main mechanisms by which antibodies exert their effects on cell cytotoxicity. After antibodies bind to the antigens on the target cells, they are bound by the Fc portion of the immune system cells and show their lethal effect against the target cells. In this context, it is essential to demonstrate the ADCC activities of antibodies in biosimilar production. However, when looking at the CDC mechanism, the complement system helps show the cytotoxicity effect. Again, complement binds to the Fc parts of the antibodies, creating holes on the cell surface and apoptosis begins.
Following the analytical comparison, which is the first step in biosimilarity comparison studies, non-clinical and clinical comparisons may need to be made, depending on necessity. - Stage of Development
- Concept stage
- Sustainable Development Goals
- Goal 9: Industry, Innovation and Infrastructure
- IPR status
- IPR granted
Partner Sought
- Expected Role of a Partner
-
The partnership model for the company, a biotechnological company seeking collaboration for their biobetter product, would ideally involve finding a partner with specific capabilities and experience. Here’s a structured approach to the partnership model:
Identification of Potential Partners:
The company should identify companies or organizations that have experience in the biotechnological or biosimilar sectors. This includes firms with a proven track record in developing and commercializing biotechnological products or biosimilars. Look for partners who have successfully conducted Phase III clinical trials or have the capability to manage clinical trials effectively.
Evaluation Criteria:
Expertise in Biotechnological Products: The partner should have experience in developing, manufacturing, and marketing biotechnological products. This ensures they understand the regulatory requirements and market dynamics specific to biologics.
Experience with Biosimilars: Partners with experience in biosimilars understand the complexities of regulatory approval processes and can leverage their knowledge to navigate similar pathways for biobetters.
Clinical Trial Capabilities: Capability to conduct Phase III clinical trials is crucial. The partner should have a strong clinical team and infrastructure to manage large-scale trials effectively.
Commercialization and Market Access: Ability to commercialize the product globally or in key markets is essential. Partners with established distribution networks and market access can expedite product launch and market penetration.
Strategic Alignment:
Ensure there is strategic alignment between the company and the potential partner regarding product development timelines, regulatory strategies, and market objectives. Consider factors such as financial stability, corporate culture, and commitment to innovation and quality.
Negotiation and Agreement:
Negotiate terms that outline responsibilities, financial arrangements (such as cost-sharing or profit-sharing models), intellectual property rights, and governance structure. Develop a clear roadmap for collaboration, including milestones for regulatory submissions, clinical trials, and commercial launch.
Implementation and Execution:
Once a partner is selected, establish clear communication channels and project management protocols. Monitor progress against milestones and adjust strategies as necessary to ensure the partnership remains on track.
Risk Management:
Identify potential risks and develop mitigation strategies jointly with the partner. Ensure both parties are committed to resolving challenges and maintaining compliance with regulatory requirements.
In summary, the company should seek a partner with a strong background in biotechnological products and biosimilars, clinical trial capabilities, and market access. A well-aligned partnership can leverage complementary strengths to accelerate the development, regulatory approval, and commercialization of their biobetter product. - Type and Size of Partner
- SME 11-49
- SME <=10
- University
- SME 50 - 249
- Type of partnership
- Research and development cooperation agreement
Call details
- Framework program
- Eureka
- Call title and identifier
-
Eurostars
- Coordinator required
-
No
- Deadline for EoI
- Deadline of the call
- Eureka
Dissemination
- Market keywords
- 04004 - Other Genetic Engineering
- Targeted countries
- All countries