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    Tumor Microenvironment (TME) targeting pH-dependent Antibody Products

    Introduction Features Services Products FAQs

    Introduction

    The tumor microenvironment (TME) is a complex and highly specialized ecosystem that is distinctly different from normal tissue. A key feature of the TME is its acidic extracellular pH, a consequence of the high rate of aerobic glycolysis in tumor cells. This low pH state is a biological signature that can be exploited for cancer therapy. Creative Biolabs' pH-dependent antibodies are engineered to bind their target antigens with high affinity specifically in the acidic TME, while having significantly reduced affinity at the neutral pH of healthy tissues. This innovative approach addresses the critical challenge of on-target, off-tumor toxicity that limits the efficacy and safety of many conventional antibody therapies.

    Targeting TME by acidic pH‑selective Antibodies

    Compared to traditional antibodies, TME-targeting pH-dependent antibodies offer distinct advantages by leveraging the unique biochemical properties of the tumor microenvironment. pH-dependent antibodies are designed with an "on-switch" that is only activated by the acidic pH of the TME. This allows the antibody to preferentially bind to the tumor, minimizing unwanted interactions with healthy tissues and dramatically reducing on-target, off-tumor toxicity. For targets with widespread expression on normal cells (e.g., VISTA or CD47), the reduced binding affinity of pH-dependent antibodies at physiological pH prevents this antigen sink effect, resulting in linear elimination kinetics, a longer half-life, and superior accumulation within the tumor. The ability to selectively accumulate at the tumor site allows for the use of potent therapeutic formats, including those that mediate strong effector functions (e.g., ADCC).

    The switch mechanism of pH-dependent antibodies. (OA Literature)Fig.1 Histidine residue constitutes a critical regulated "switch" in pH-dependent antibodies.1

    Production of TME-targeting pH-dependent Antibodies

    The mechanism of action is often driven by histidine residues in the antibody's paratope, which change their charge state in response to the pH shift, enabling high-affinity binding in the acidic TME. Creative Biolabs offers a comprehensive and streamlined workflow for the design, production, and characterization of TME-targeting pH-dependent antibodies. Our process is transparent and designed to accelerate your project from initial concept to final deliverable.

    pH-dependent Antibody Production

    01Computational Design

    Rational Design: Identify and mutate amino acid residues to create pH-dependent binding.

    02Library Generation

    Library Creation: Generate phage or yeast display library with targeted mutations.

    03Dual-pH High-Throughput Screening

    Positive Selection: Screen binders with high affinity at acidic pH.

    Negative Selection: Retain binders with low affinity at neutral pH.

    04Candidate Characterization

    In Vitro Analysis: Measure binding kinetics at different pH levels.

    Cell-based Assays: Confirm functional efficacy on target cells.

    05In Vivo Efficacy & Safety Assessment

    Animal Models: Assess tumor accumulation and pharmacokinetics in animal models.

    Safety Evaluation: Confirm the antibody's superior therapeutic index.

    06Final Deliverable Preparation

    pH-dependent Antibodies: optimized sequences and antibody products.

    Data Reports: Project reports including pH-selectivity assays, cell-based assays, and in vivo results.

    Our TME-targeting pH-dependent Antibody products

    Creative Biolabs is a leader in next-generation antibody therapeutics, and our pH-dependent antibody platform is a testament to our commitment to innovation. Our unique approach to protein engineering allows us to design antibodies that solve the core problems of on-target, off-tumor toxicity and poor pharmacokinetics. We use advanced rational design complemented by cutting-edge display technologies to create highly selective and potent therapeutics. Our expertise in pH-dependent antibody engineering provides a powerful new tool for tumor targets research. To learn more about how our pH-dependent antibody platform can advance your project, please contact us.


    ME-targeting Immune Checkpoint Inhibitors

    pH-dependent antibodies have shown superior therapeutic profiles. For instance, a pH-dependent anti-CTLA-4 antibody has demonstrated equivalent anti-tumor efficacy with significantly reduced systemic toxicity and T cell activation outside the tumor.

    Antibody-Drug Conjugates (ADCs)

    pH-dependent antibodies can serve as the targeting moiety for ADCs, ensuring the toxic payload is released primarily within the acidic TME. This approach enhances the therapeutic index and mitigates the risk of widespread cytotoxicity.

    TME-targeting CAR-T
    Cells

    The pH-dependent binding domain (scFv) can be integrated into chimeric antigen receptor (CAR) constructs for CAR-T cell therapy. This is a promising strategy for enhancing the safety and efficacy of CAR-T cell therapy against solid tumors.

    FAQs

    How do Creative Biolabs' pH-dependent antibodies compare to conventional antibodies?

    Our pH-dependent antibodies are engineered to be "off" in normal tissue (neutral pH) and "on" in the acidic tumor microenvironment. This provides a significant advantage in tumor-specific targeting and reduces systemic side effects and drug clearance, which are common issues with conventional antibodies that bind indiscriminately.

    Can your pH-dependent technology be applied to any antigen?

    Our platform is highly adaptable. While the success of rational design is enhanced by available structural information, our agnostic screening approaches from diverse libraries allow us to discover pH-dependent binders for a wide range of antigens, including those that do not have an intrinsically pH-sensitive binding domain.

    Can your technology improve the efficacy of my existing therapeutic antibody?

    Yes, absolutely. We can take an existing antibody and use our structure-based engineering platform to introduce pH-dependent binding while preserving its original epitope and high-affinity binding in the TME. This can improve its safety profile and pharmacokinetics without compromising its therapeutic function.

    What about the stability and manufacturability of pH-dependent antibodies?

    Our production process includes rigorous biophysical characterization using techniques like DSC and analytical ultracentrifugation to ensure that the engineered pH-dependent mutations do not compromise the antibody's folding stability or aggregation behavior, ensuring it is suitable for manufacturing and use.

    Reference

    1. Smith, F. Donelson, et al. "Conditionally active, pH-sensitive immunoregulatory antibodies targeting VISTA and CTLA-4 lead an emerging class of cancer therapeutics." Antibodies 12.3 (2023): 55. Distributed under Open Access license CC BY 4.0, without modification. https://doi.org/10.3390/antib12030055
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