Creative Biolabs facilitates immuno-oncology research by identifying novel modulators of immune checkpoints. We utilize function-forward screening to find antibodies and peptides that can release the brakes on the immune system or fine-tune its response. Our services are designed to accelerate the discovery of next-generation immunotherapies. We offer a comprehensive solution for finding molecules that can unleash the power of the immune system against cancer. Central to our approach is our expertise in Functional Phage Display Screening, a platform that selects candidates based on their real biological impact in sophisticated cellular models. Our platform for discovering novel immune checkpoint modulators facilitates:
The immune system is equipped with a series of checkpoints—molecular brakes that prevent it from attacking the body's own healthy cells. These checkpoints are crucial for maintaining self-tolerance and preventing autoimmune disease. However, many cancers have learned to hijack these mechanisms. By expressing specific proteins (ligands) on their surface, tumor cells can engage with checkpoints on immune cells and effectively switch them off, creating an immunosuppressive shield that allows the tumor to grow undetected. Immune checkpoint inhibitor (ICI) therapies, such as anti-PD-1 and anti-CTLA-4 antibodies, have revolutionized cancer treatment. These drugs block the "off" signals, unleashing the immune system to recognize and destroy cancer cells. Despite this success, significant challenges remain. A large number of patients do not respond to existing therapies, and many who initially respond eventually develop resistance. Furthermore, the broad-acting nature of current ICIs can lead to significant immune-related adverse events.
Fig.1 Therapeutic strategies for targeting immune checkpoints.1
The next great leap in immuno-oncology requires moving beyond the known checkpoints. The key challenges are to:
Addressing these challenges requires a discovery platform that can probe the complex interactions between immune cells and cancer cells and select for molecules based on a functional outcome, such as restored T-cell killing activity.
At Creative Biolabs, we have developed a portfolio of services specifically for the discovery of novel immune checkpoint modulators. Our approach is built on using complex, biologically relevant co-culture assays that mimic the interaction between immune cells and tumor cells. We focus on identifying molecules that produce a measurable, therapeutically desirable change in immune cell function. Our specialized service offerings include:
Our workflow is a systematic, four-phase process engineered to ensure the identification of high-quality, functional immune modulators. Each step is precisely adapted to the complexities of immune cell biology.
A successful project begins with a robust experimental design. In this crucial first phase, we collaborate with you to define the project's objectives. This includes selecting the appropriate effector cells (e.g., primary human T-cells, NK cells) and target cells (e.g., cancer cell lines engineered to express specific ligands). We then design the functional co-culture system and establish the key functional readouts, such as IL-2 secretion or target cell killing, which will serve as the basis for selection.
This is where true functional discovery happens. The phage library is introduced into the co-culture system. Instead of selecting for simple binding, we choose a biological event. For instance, we might use a reporter system where T-cell activation leads to a fluorescent signal, and then use FACS to isolate only the tumor cells that are bound by phages and are successfully activating T-cells. Through successive rounds of this stringent functional pressure, we enrich for phage candidates that directly modulate the immune response in the desired way.
After enriching for a population of functionally active phages, we identify the displayed molecules. Our high-throughput process relies on the advanced capabilities of our Phage Display NGS Service. Deep sequencing provides a complete picture of the selected candidates, quantifying the enrichment of each unique clone. Our bioinformatics team analyzes this data to identify promising sequences and clusters, which are then prioritized for validation.
The top candidate sequences identified through NGS are synthesized and produced as purified proteins. These molecules are then rigorously validated in a panel of immunoassays. We confirm their ability to block receptor-ligand interactions, stimulate cytokine release, enhance T-cell proliferation, or promote tumor cell killing. You receive a comprehensive data package with all sequence information and functional validation results, along with the validated molecules for your downstream development.
Phage display technology is built upon the biology of bacteriophages, which are viruses that specifically infect bacteria. These entities are ubiquitous in nature, from deep oceans where sea phages thrive to the human gut, where a phage symbiote relationship exists with our microbiome. We use well-characterized phages like the enterobacteria phage p1 or derivatives of M13, a temperate phage that can replicate without immediately killing its host. By inserting a gene for a human protein into the phage's DNA, we can compel the phage to display that protein on its surface. This creates a direct link between the protein (phenotype) and its gene (genotype), allowing for the rapid screening of billions of molecules to find one with a desired function.
Creative Biolabs has built a comprehensive infrastructure to support your discovery program from concept to validated lead.
Choosing Creative Biolabs provides a decisive advantage in the competitive field of immunotherapy development.
The discovery of novel immune checkpoint modulators has profound implications for treating a wide range of diseases.
Many cancers, known as "cold" tumors, are not infiltrated by T-cells and thus do not respond to traditional checkpoint inhibitors. Our platform can discover agonists for co-stimulatory receptors or modulators of novel pathways that can attract and activate immune cells within the tumor microenvironment. A therapeutic based on such a molecule could be used as a sensitizing agent, transforming a non-responsive tumor into one that can be effectively eliminated by the immune system or other therapies like anti-PD-1.
The future of immuno-oncology lies in intelligent combinations. A novel checkpoint inhibitor discovered through our service could be paired with an existing anti-PD-1 or anti-CTLA-4 antibody to achieve deeper, more durable responses by blocking multiple immunosuppressive pathways simultaneously. Alternatively, an agonist of a co-stimulatory molecule could be combined with a cancer vaccine to dramatically enhance the generation of tumor-specific T-cells.
The same principles used to activate the immune system against cancer can be reversed to suppress it in cases of autoimmunity. Our functional screens can be adapted to identify "inverse agonists" or "blocking antibodies" for co-stimulatory pathways that are overactive in diseases like rheumatoid arthritis or lupus. This allows for the development of highly specific immunomodulators that can restore balance to the immune system without causing broad immunosuppression.
The next breakthrough in immunotherapy is waiting to be discovered. Our functional screening platform provides the most direct path to identifying novel checkpoint modulators that can overcome current therapeutic limitations and unlock the full potential of the immune system. If you have any questions about our service details, please feel free to today to discuss your project and receive a tailored proposal.
Can your platform be used to find modulators for a specific, known immune checkpoint receptor?
Yes, absolutely. While our platform excels at unbiased discovery, it is also perfectly suited for targeted projects. We can develop a highly specific functional screen centered on your receptor of interest. For example, we can engineer a cell line to express your target receptor and a reporter gene that activates upon signaling. We then screen for phage-displayed molecules that either block or induce that signal, allowing us to find highly potent and specific antagonists or agonists for your known target.
What is the typical starting material for an immune cell-based screen?
For most immuno-oncology projects, we recommend using primary human immune cells, such as T-cells isolated from peripheral blood mononuclear cells (PBMCs) from healthy donors. This provides a highly relevant biological system. We can use either total T-cell populations or isolate specific subsets, like CD8+ cytotoxic T-cells, depending on the project's goals. This use of primary cells ensures that the modulators we discover are active in a system that closely resembles human physiology.
How do you distinguish between a molecule that is toxic to the tumor cells versus one that is activating the T-cells to kill them?
This is a critical control that is built into our validation phase. A lead candidate is first tested for direct cytotoxicity against the tumor cells in the absence of any immune cells. This establishes a baseline for any direct anti-tumor effects. We then perform the co-culture killing assay. A true immune modulator will show significantly enhanced killing only when both the T-cells and tumor cells are present, confirming that its mechanism of action is through the activation of the immune cells and not direct toxicity.
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Please kindly note that our services can only be used to support research purposes (Not for clinical use).
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