Soluble Antigen targeting pH-dependent Antibody Products

Introduction

Conventional antibodies for soluble antigens often require high doses and frequent administration because the formation of stable immune complexes with the antigen can lead to its accumulation in the bloodstream. This is because the complex is recycled back to circulation via the FcRn receptor instead of being degraded. Our platform addresses this by engineering antibodies that bind strongly at neutral pH (in the blood) but release the antigen in the acidic endosome for degradation, allowing the antibody to be recycled and reused, thereby improving the duration of antigen neutralization.

Fig.1 Recycling mechanism of pH-dependent antibody binding to antigen. ¹

pH-dependent Antibody for Soluble Antigen Sweeping

The pH-responsive antibody engineered to release their bound antigen in acidified endosomes. They function in a continuous cycle of binding the antigen in the neutral extracellular fluid, being endocytosed, releasing the antigen in the acidic endosome, and then being recycled back to the extracellular fluid to bind to the antigen again. This dissociation of the antigen at an acidic pH allows the free antigen to be trafficked to the lysosome for degradation, while the antibody itself is protected and recycled. The pH-dependent antibodies offer distinct advantages and allow them to be applied across a wide range of therapeutic areas.

Our pH-dependent Antibodies Targeting Soluble Antigens

Creative Biolabs' advanced platform represents the next generation of antibody therapeutics, offering a versatile and highly effective solution for soluble antigen challenges. Our production process is designed to be comprehensive and transparent, providing clients with a clear pathway from initial concept to final product.

Our key advantages and unique features include:

• Proven Multi-modal Engineering: We combine advanced variable region engineering, such as light-chain shuffling, with proprietary Fc engineering for enhanced FcγRIIb and FcRn binding and strategic charge substitutions.
• In-depth Mechanistic Understanding: Our team has an in-depth understanding of the complex interplay between the antibody, antigen, and cellular recycling pathways. We know that the antigen's own biophysical attributes can affect the cellular handling of the complex, which allows us to design more effective and predictable therapeutics.
• Broad Therapeutic Efficacy: Our platform has been successfully applied to a diverse range of soluble antigens, from highly abundant endogenous proteins like C5 to exogenous bacterial superantigens like SEB and snake venom toxins.

Fig.2 Selection strategy for pH-dependent antibodies. ¹

Published Data

A new strategy, light-chain shuffling, for pH-dependent antibody development has been reported that combined with phage display technology to generate or enhance pH-dependent antigen-binding properties without artificially introducing histidine residues. This method involves taking the variable heavy chain (VH) of a parental antibody and combining it with a library of different variable light chains (VL) to create a diverse collection of single-chain variable fragments (scFvs).

Fig.3 Phage display selection and binding of pH-dependent antibodies.²

Contact Us

Creative Biolabs is your partner in next-generation antibody therapeutics. Our proven pH-dependent antibody platform offers a unique and powerful solution to the long-standing challenge of soluble antigen targeting. By enabling a "catch and release" mechanism and leveraging multi-faceted engineering, we provide a pathway to more effective and safer. Contact us to discuss your specific program.

FAQs

References

1. Ledsgaard, Line, et al. "Advances in antibody phage display technology." Drug discovery today 27.8 (2022): 2151-2169. Distributed under Open Access license CC BY 4.0. The image was modified by extracting and using only Part A or B of the original image. https://doi.org/10.1016/j.drudis.2022.05.002
2. Tulika, Tulika, et al. "Engineering of pH-dependent antigen binding properties for toxin-targeting IgG1 antibodies using light-chain shuffling." Structure 32.9 (2024): 1404-1418. Distributed under Open Access license CC BY 4.0. The image was modified by extracting and using only Part B-E of the original image. https://doi.org/10.1016/j.str.2024.07.014

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