Multivalent Single Domain Antibody (SdAb) Development Service

Introduction Multivalent VHH Generation Clinical Use Features Case Study Published Data FAQ Resources

Creative Biolabs has long been an expert in the field of single domain antibody (sdAb) discovery and development. With years of experience and the novel MUsdAb™ platform, our scientists can develop multivalent VHH antibodies in a variety of formats to meet your specific project demands.

Introduction

VHH, generated from the VHH domain of heavy-chain antibodies found in camelids (e.g. dromedaries, camels, llamas, and alpacas) or the VNAR domain of cartilaginous fish (such as sharks), represent the smallest antibody fragments. These fragments offer numerous advantages as potential candidates for therapeutic or diagnostic applications. Thanks to their small size, high permeability, and extreme stability, VHH antibodies are also excellent modules for engineering modifications. Currently, multivalent VHH antibodies (e.g. bispecific VHHs) show great promise as more effective alternatives to conventional scFv/Fab/IgG-based bispecific antibodies.

Generation of Multivalent VHH

The development of multivalent VHH antibodies has a significant impact on medicine. As an ideal module for generating bispecific and multi-specific antibody molecules, multivalent VHH development provides various alternative antibody formats with optimized architectures. Creative Biolabs has built the novel MUsdAb™ platform specifically for the generation of multivalent VHHs. By fusing VHHs with other antibody fragments, Fc fragments, or specific constructs, a series of multivalent VHHs can be designed without compromising their original target-binding affinity. Our scientists work closely with you to understand your core requirements and deliver the most suitable solution to achieve your goals.

Fig.1 VHH module with various engineering formats.Fig.1 VHH module with various engineering formats.1,3

Multivalent VHH in Clinical Trials

Currently, several multivalent VHH antibodies with different tandem formations in clinical trials. For instance, there is a bivalent monospecific VHH targeting von Willebrand factor (vWF) with no half-life extension; a trivalent bispecific VHH targeting vWF with HSA binding ability and half-life extension; a bivalent bispecific VHH targeting IL6R with HSA binding ability; and a trivalent VHH targeting IL-17F and IL-17A/F with HSA binding ability. Additionally, HER2-S-Fab has demonstrated potent tumor growth inhibition in human tumor xenograft models. In brief, the multivalent VHH antibodies are becoming increasingly important in drug discovery. With our extensive experience in VHH development, Creative Biolabs can help you achieve even the most challenging design and validations for unique multivalent VHHs.

Fig.2 Multivalent VHHs with different tandem formationsFig.2 Multivalent VHHs with different tandem formations.

Features of Multivalent VHH

Creative Biolabs is committed to assisting VHH development projects with high quality and efficiency. With our well-established MUsdAb™ platform and experienced scientists, we are confident in tailoring the best solutions to develop multivalent VHH for your projects. If you are interested in learning more, please feel free to contact us.

Published Data

Multiple Applications of Multivalent VHHs in Disease Treatment

Fig. 3 Therapeutic Potential of Multivalent VHHs Targeting Cancer Antigens.Fig. 3 Therapeutic Potential of Multivalent VHHs Targeting Cancer Antigens.2,3

Multivalent VHHs have shown tremendous potential in disease treatment, due to their unique structural and functional properties. Their small molecular size allows them to maintain the same high specificity and affinity as traditional monoclonal antibodies while offering significant improvements in tissue penetration and bioavailability. Multivalent VHHs have the potential to enhance therapeutic efficacy and prevent drug resistance by targeting multiple antigen epitopes on cancer cells. Moreover, multivalent VHHs have shown promising results in treating autoimmune and infectious diseases. For example, they may reduce inflammatory responses by inhibiting several signaling pathways simultaneously or halt disease progression by neutralizing pathogen-produced toxins. As VHH technology continues to evolve, an increasing number of multivalent VHH drugs are expected to advance to clinical trials, expanding the range of treatment options available to patients.

References

  1. Iezzi, María Elena, et al. "Single-domain antibodies and the promise of modular targeting in cancer imaging and treatment." Frontiers in Immunology 9 (2018): 273.
  2. Wang, Jiewen, et al. "Research progress and applications of multivalent, multispecific and modified VHHs for disease treatment." Frontiers in immunology 12 (2022): 838082.
  3. under Open Access license CC BY 4.0, without modification.

FAQ

1. How can VHHs be created with multivalency?
VHHs can be engineered for multivalency through various genetic techniques. One method involves connecting several VHH domains with flexible peptide linkers, creating a series of repeated units. Another approach is to fuse VHHs to the Fc regions of conventional antibodies or other protein scaffolds, enabling the display of multiple VHH domains for simultaneous binding.
2. What are the challenges in producing multivalent VHHs?
Key challenges include maintaining the stability of linked VHH units, ensuring correct folding and functional expression in host systems, avoiding steric hindrance that may affect binding, and optimizing linker length to balance flexibility with structural integrity. Additionally, achieving reliable and high-yield synthesis in mammalian or microbial expression systems can be difficult.
3. How does the linker affect the functionality of multivalent VHHs?
In multivalent VHHs, the linker is essential to preserving the orientation and flexibility of each VHH domain, ensuring that they can access their target antigen-binding sites. A well-designed linker enhances binding affinity and specificity by preventing steric collision and allowing the domains to move freely, facilitating interaction with multiple antigen sites simultaneously.
4. How can multivalent VHHs improve cancer treatment outcomes?
Multivalent VHHs enhance cancer treatment by targeting numerous epitopes on cancer cells at the same time, increasing cell binding and internalization. This multivalent interaction can improve the efficacy of targeted cytotoxic drug delivery, immunomodulation, and growth factor receptor blockade. The improved specificity and avidity lower non-specific toxicity and increase the therapeutic index.
5. What are the potential future directions for multivalent VHH research and development?
The prospect for multivalent VHH research is promising, with continuous efforts to improve specificity, stability, and multifunctionality. Future directions include investigating novel formats and fusion proteins, applying advanced bioengineering techniques like CRISPR for precise modifications, expanding applications in neurology and autoimmune diseases, and developing innovative gene therapy delivery systems. Collaborations with biotech and pharmaceutical companies will accelerate the translation of research into therapeutic applications.
6. How can multivalent VHHs be applied in infectious disease diagnostics?
Multivalent VHHs can enhance the sensitivity and specificity of infectious disease diagnostics by binding to multiple epitopes on a pathogen or toxin. This multivalency can improve signal generation in platforms such as ELISA, lateral flow assays, and biosensors, enabling more accurate detection of low-abundance targets and improving diagnostic test performance in clinical and field situations.

Resources

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