Introduction Published Data What We Can Offer? Workflow Why Choose Us? FAQs Related Products Services
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The complement system is a crucial component of the innate immune system, playing a significant role in host defense. However, its dysregulation is implicated in a wide range of diseases, from autoimmune disorders to neurodegeneration and cancer. Creative Biolabs' specialized therapeutic antibody development services offer a powerful solution.
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Introduction
The complement system, a complex network of over 50 proteins and receptors, functions as a first-line defense against pathogens. It operates through three main activation pathways: the classical, lectin, and alternative pathways, all converging on the cleavage of complement component C3. The central role of C3 and downstream components like C5 has made them attractive targets for therapeutic intervention. While complement activation is essential for immunity, its dysregulation can lead to tissue damage and chronic inflammation, contributing to a wide array of pathological conditions.
Fig.1 Mechanism of action of anti-CD38.1,3
Therapeutic antibodies have emerged as a powerful modality to modulate the complement system. Unlike small-molecule inhibitors, antibodies offer exceptional specificity and a prolonged half-life. They can be designed to block the activation of specific complement components, such as C5, or to inhibit key enzymes like Factor D. For instance, antibodies targeting C5 can prevent the formation of the terminal membrane attack complex (MAC), which is responsible for cell lysis. Furthermore, antibodies can leverage complement-dependent cytotoxicity (CDC) or complement-dependent cell-mediated cytotoxicity (CDCC) as their therapeutic mechanism, particularly in oncology, to specifically target and eliminate tumor cells. Scientific literature highlights the nuanced roles of the complement system in various diseases, reinforcing the need for highly specific and effective therapeutic interventions.
Utilizing its advanced technology and extensive experience, Creative Biolabs provides a comprehensive range of therapeutic antibody development services. Our offerings encompass:
We specialize in generating antibody candidates that block the terminal cascade of C5, a well-researched component. Our antibodies prevent inflammation and cell damage while preserving beneficial functions. Furthermore, we can design agents, like humanized single-chain monoclonal fragments, to reduce cardiac surgery complications by inhibiting C5's cleavage.
Our services also extend to developing antibodies targeting the CD20 protein. For instance, we engineered a human monoclonal antibody that targets a unique epitope. Laboratory studies demonstrate this antibody lyses CLL cells and B-cell lines with low CD20 counts much more effectively than several commercially available alternatives.
Also known as membrane cofactor protein (MCP), CD46 acts as a complement receptor that inhibits the system. Its crucial function is to protect host cells from damage caused by their own complement, making it a prime subject for therapeutic antibody research.
CD55, or decay-accelerating factor (DAF), is a glycosylphosphatidylinositol (GPI)-anchored membrane protein. It blocks activation in both the classical and alternative complement pathways. Serving as a membrane-bound complement inhibitor, it protects native cells from the damaging effects of their own complement.
Recognized as MAC-inhibitory protein (MAC-IP), membrane inhibitor of reactive lysis (MIRL), or protectin, CD59 functions as a complement receptor that inhibits the process. It shields host cells from self-destruction via complement-mediated lysis and represents a promising new target for therapeutic antibody research.
Published Data
Fig.2 CDC assay on human CD20+ cells of different sensitivity to anti-CD20 mAbs and CLL cells freshly isolated from patients.2,3
The study utilized a series of experiments to demonstrate that an anti-CD20 mab's ability to induce complement-dependent cytotoxicity (CDC) is contingent on its concentration and ability to form large clusters on the cell surface. Using two human lymphoma cell lines, Raji and Ramos, the researchers compared the effects of the Type II antibody with those of a Type I antibody. Flow cytometry was used to analyze antibody binding and CDC induction. The results showed that while the Type I antibody efficiently induced CDC across a wide range of concentrations, the Type II antibody only demonstrated significant CDC activity at high concentrations. Confocal microscopy and Western blotting confirmed that at high concentrations, the Type II antibody formed large aggregates on the cell membrane, a process inhibited by a lysosome blocker. This clustering, the data revealed, was essential for the subsequent recruitment of complement component C1q, a key step in activating the complement cascade. This finding suggests that a novel, concentration-dependent mechanism is at play, where the Type II antibody transitions from a non-CDC inducer to an effective one by physically organizing CD20 receptors, thereby facilitating complement activation and tumor cell death.
What We Can Offer?
To support your therapeutic antibody development needs, Creative Biolabs provides a comprehensive suite of products and services tailored to targeting the complement system.
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Target Antigen Production: High-quality recombinant proteins for complement-related targets to facilitate antibody discovery.
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Antibody Discovery Services: Including hybridoma and phage display platforms for generating diverse antibody panels.
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Antibody Engineering: Custom services for antibody humanization, affinity maturation, and the development of bispecific antibodies.
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Functional Assays: A full panel of in vitro assays to evaluate antibody function, including complement inhibition, cell-based assays, and binding kinetics analysis.
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Lead Optimization and Characterization: Detailed biophysical and biochemical characterization to select the best lead candidates.
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Custom Antibody Production: Large-scale antibody production services for research or clinical trial use.
Workflow
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Target Validation and Antigen Preparation: We validate the therapeutic target and prepare high-quality antigens for antibody generation.
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Antibody Discovery: We screen for and identify diverse, high-affinity antibodies using advanced platforms like hybridoma and phage display.
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Antibody Engineering and Humanization: Lead antibodies are engineered for improved affinity, stability, and manufacturability, with humanization to reduce immunogenicity.
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Functional Validation: Antibodies are rigorously tested in in vitro assays to confirm their intended function and therapeutic potential.
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Lead Optimization and Characterization: The best candidates are optimized for manufacturability and characterized for binding kinetics, epitope mapping, and stability.
Why Choose Us?
At Creative Biolabs, our deep understanding of the complement system, combined with our advanced technology platforms, sets us apart. We are committed to providing our clients with robust and effective solutions for their therapeutic antibody development needs.
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Exceptional Scientific Expertise: Our team of experienced scientists possesses a profound knowledge of the complement system's intricate pathways and its role in disease. We leverage this expertise to design and execute highly effective development strategies.
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Cutting-Edge Technology: We utilize state-of-the-art platforms for antibody discovery, engineering, and functional validation, ensuring the highest quality and success rate for your project.
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Streamlined and Efficient Workflow: Our optimized workflow is designed to accelerate the development timeline, providing you with a high-quality lead candidate in a timely manner.
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Proven Track Record: Our dedication to quality and results is evidenced by our success in past projects and our contributions to scientific literature, supported by published data.
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FAQs
Q: How do therapeutic antibodies target the complement system?
A: Therapeutic antibodies can be designed to specifically bind to a component of the complement system. By doing so, they can either block the protein's function, inhibit its interaction with other molecules, or prevent the activation of an entire pathway, thereby preventing unwanted inflammation and tissue damage.
Q: What types of diseases can be treated with this approach?
A: This approach is highly promising for a wide range of diseases driven by complement dysregulation. This includes various autoimmune disorders, such as certain forms of arthritis and kidney diseases, as well as neurodegenerative conditions and even some types of cancer.
Q: Why is targeting the complement system with antibodies more effective than other methods?
A: Antibodies offer a high degree of specificity, meaning they can precisely target the intended protein without affecting other critical biological processes. This can lead to fewer off-target side effects compared to broader-acting small molecule inhibitors. Additionally, antibodies typically have a longer half-life, allowing for less frequent dosing.
Q: What are the potential challenges in developing these antibodies?
A: The complex nature of the complement cascade can make it challenging to design an antibody that effectively modulates the system without causing unintended side effects. It is crucial to have a deep understanding of the target and its role in the specific disease to ensure a successful therapeutic outcome.
Q: What data should I expect to see from a development project like this?
A: A comprehensive project should provide you with data demonstrating the antibody's binding affinity, specificity to the target, and its functional activity in inhibiting or activating the complement pathway as intended. You should also receive information on the antibody's stability and manufacturability.
Creative Biolabs is a leader in therapeutic antibody development, offering comprehensive services tailored to your specific project needs. Our expertise in targeting the complement system, combined with our advanced platforms and a commitment to quality, ensures that we can help you accelerate your drug discovery efforts. Whether you are at the initial discovery stage or need help with lead optimization, our team is ready to assist.
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References
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Chen, Zhiyi et al. "Application of CD38 monoclonal antibody in kidney disease." Frontiers in Immunology vol. 15 1382977. 10 May. 2024, https://doi.org/10.3389/fimmu.2024.1382977
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Kuźniewska, Alicja et al. "The Acquisition of Complement-Dependent Cytotoxicity by the Type II Anti-CD20 Therapeutic Antibody Obinutuzumab." Cancers vol. 16,1 49. 21 Dec. 2023, https://doi.org/10.3390/cancers16010049
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