Modern biotherapeutic research is shifting. Scientists are moving beyond traditional full-length antibodies to explore smaller, more stable, and versatile binding formats. At the forefront of this shift is the single domain antibody (sdAb), also widely known as VHH. These molecules offer unique properties that solve many limitations of conventional immunoglobulins.
Creative Biolabs is a premier camelid antibody discovery CRO dedicated to advancing your specific research programs. Our platform specializes in the generation of high-affinity VHHs using advanced phage display technology. We focus on two critical areas of application: molecular imaging and therapeutic research. Our team provides a comprehensive VHH discovery service. We handle everything from animal immunization to the delivery of sequenced, high-affinity binders. Beyond VHHs, our phage display capabilities extend to next-generation biologic leads across modalities—including scFv, Fab, and peptide scaffolds—through our integrated Phage Display for Next-Generation Biologic Leads Platform. We understand the biological nuances of the heavy chain antibody found in camelids and use this knowledge to build libraries that yield successful candidates for your projects.
Technical Insights: The Science Behind VHH
What is a VHH or sdAb?
To understand the value of our service, we must first look at the biology. Most mammals produce antibodies composed of two heavy chains and two light chains. However, members of the Camelidae family (camels, llamas, and alpacas) produce a distinct type of antibody. This is the camelid antibody, specifically the heavy chain antibody (hcAb). These antibodies lack light chains entirely. They also lack the CH1 domain in their heavy chains. The antigen-binding site is formed by a single variable domain. This isolated domain is what we refer to as the VHH (Variable Heavy Homodimers) or sdAb.
Key Advantages of VHH Molecules
Small Size: They are approximately 15 kDa in size. This is about one-tenth the size of a conventional IgG.
High Stability: They resist heat, pH changes, and denaturing agents better than most antibody fragments.
Solubility: They are highly soluble and do not tend to aggregate.
Access to Cryptic Epitopes: They have a long Complementarity Determining Region 3 (CDR3). This loop can extend into cavities on antigens (like enzyme active sites) that flat IgG surfaces cannot reach.
Tissue Penetration: Their small size allows them to penetrate tissues and solid tumors rapidly.
Comparison: VHH vs. scFv vs. IgG
Fig.1 Structural comparison: conventional IgG, scFv, and camelid VHH.1,3
To help you decide if VHH is right for your project, look at this comparison.
Feature
IgG (Conventional)
scFv (Single Chain Fv)
VHH / sdAb
Size
~150 kDa
~25-30 kDa
~12-15 kDa
Chains
2 Heavy, 2 Light
1 Heavy + 1 Light (Linked)
1 Heavy Domain Only
Stability
Moderate
Low (prone to aggregation)
High
Solubility
Good
Moderate
Excellent
Tissue Penetration
Slow / Low
Moderate
Rapid / High
Clearance
Slow (Weeks)
Moderate
Fast (Hours)
Library Types Available
We offer different strategies depending on your timeline and targets.
Fig.2 Construction strategies for natural, semi-synthetic, and fully synthetic antibody phage libraries.2,3
Immune Libraries: This is our gold standard. We immunize an alpaca or llama antibody host with your specific antigen. This yields the highest affinity as the binders are matured in the animal. It is ideal for difficult targets or therapeutic VHH discovery.
Naive Libraries: These libraries are built from the B-cells of many non-immunized animals. They are fast (no immunization needed) and good for non-immunogenic or toxic antigens.
Synthetic Libraries: These are designed in the computer and built in the lab by randomizing the CDR regions of a stable VHH framework. They offer huge diversity and are fully defined, making them perfect for highly specific selection requirements.
Why Phage Display for VHH?
Speed: We can screen libraries with billions of variants in a few weeks.
Diversity: We capture the full immune repertoire of the animal.
Control: We can control the selection conditions to favor high affinity or specificity.
Our Phage Display Technology Platform
We utilize phage display as our primary engine for VHH discovery service. Phage display is a robust technique that links the genotype (gene) to the phenotype (protein). In our workflow, we clone the VHH genes from camelid B-cells (or use synthetic designs) and insert them into a phage vector. The phage then displays the VHH protein on its surface. This physical link allows us to screen billions of different antibodies to find the one that binds to your target.
Our Service Workflow
Phase I
Immunization (or Design)
We invoke a strong immune response or design a synthetic repertoire.
Phase II
Library Construction
We perform alpaca VHH library construction by isolating RNA and cloning VHH regions.
Phase III
Bio-panning
We expose the library to your antigen, washing away non-binders and enriching for high-affinity candidates.
Phase IV
Screening
We identify unique binders via ELISA and sequencing.
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Versatile Applications of VHH
The unique properties of VHH molecules—small size, high stability, and deep tissue penetration—make them powerful tools across multiple research disciplines.
Imaging Research
SdAb generation for imaging is a rapidly growing field. Conventional antibodies circulate in the blood for days, creating high background noise. You often have to wait a long time for the background to clear before you can see the target clearly. VHH molecules solve this. Because they are small, they clear from the blood very quickly (often within hours) but bind tightly to the target. This creates a high signal-to-noise ratio, allowing for same-day imaging in research settings. We can conjugate your VHHs to radioisotopes, fluorescent dyes, or paramagnetic particles.
Therapeutic Research
While our services are for research use only, we support the early stages of therapeutic VHH discovery. Researchers use our platform to identify leads for:
Enzyme Inhibition: The long CDR3 loop of a VHH can access and block active sites that flat IgGs cannot reach.
Bispecific Formats: You can easily link two different VHHs to create a bispecific molecule (e.g., one binding a tumor, one binding an immune cell).
CAR-T Development: VHHs serve as excellent, stable binding domains for Chimeric Antigen Receptor (CAR) T-cell constructs.
Why Choose Our VHH Discovery Service?
Selecting a vendor for sdAb generation is a major decision. Here is why researchers trust us.
Deep Expertise in Camelid Immunology
We do not just treat alpacas and llamas as tools. We understand the biology of the camelid antibody. We know how to primer-design specifically for the different IgG subclasses in these animals to ensure we only amplify the VHH and not the conventional heavy chains.
Customizable Screening Strategies
Our strategies can be tailored to fit your needs:
- Do you need a VHH that releases at low pH? We can screen for that.
- Do you need a VHH that binds in the presence of high salt? We can adjust the wash buffers.
- Do you need cross-species reactivity (binds both human and mouse protein)? We can perform alternating panning rounds.
Complete Transparency
You own the data. We provide the full DNA sequences of the identified binders. We also provide detailed reports on the alpaca VHH library construction metrics, including library size and insert rate.
The versatility of the VHH makes it an essential tool for modern biological research. Whether you are pursuing sdAb generation for imaging clarity or exploring mechanisms for therapeutic VHH discovery, our platform is ready. We combine the natural diversity of the llama antibody immune system with the precision of phage display. This results in binders that are stable, specific, and high-affinity. Contact us today to discuss your target. Let our experts design a single domain antibody library strategy that fits your research goals. We look forward to accelerating your discovery process.
Contact Our Experts
Published Data1,3
A recent review published in 2023 provides a comprehensive analysis that explores why VHH molecules are uniquely positioned for rapid research intervention models, particularly when speed and adaptability are paramount. The authors emphasize that the inherent stability and modular nature of VHHs allow for advanced engineering strategies that remain difficult to achieve with conventional immunoglobulins. A significant portion of the review details the construction of multivalent and biparatopic VHHs, where multiple binding domains are linked together to enhance potency. This structural flexibility enables researchers to significantly increase binding avidity and neutralization capacity against complex viral targets. Furthermore, the literature highlights the versatility of VHHs regarding administration routes. Due to their robust solubility and resistance to denaturation, these molecules are suitable for alternative delivery methods, such as nebulization for direct inhalation in research models. The review concludes that the combination of these physical properties with the high-throughput screening capabilities of phage display establishes a powerful pipeline for therapeutic VHH discovery, allowing for the rapid identification of binders against cryptic or conserved epitopes.
Frequently Asked Questions (FAQ)
Q: Can you perform immunization if I do not have the protein?
A: Yes. We can produce the protein antigen for you in our lab. Alternatively, we can use DNA immunization or cell-based immunization for our VHH discovery service.
Q: Do you use Llamas or Alpacas?
A: We can use either. Both produce the heavy chain antibody. Alpacas are often easier to handle, but Llamas are larger and can provide more serum. We can advise on the best choice for your project.
Q: What is the difference between an sdAb and a VHH?
A: They are essentially the same in this context. VHH stands for the Variable domain of the Heavy chain of Heavy-chain-only antibodies. sdAb stands for Single Domain Antibody. All VHHs are sdAbs, but sdAb is a broader term that can technically include engineered human domains (though VHH is the most common natural form).
Q: How do you deliver the final product?
A: We typically deliver the plasmid DNA containing the VHH sequences, a report of the sequences, and a small amount of purified VHH protein for your internal validation.
Reference:
Daly, Janet M., Theam Soon Lim, and Kevin C. Gough. "Therapeutic phage display-derived single-domain antibodies for pandemic preparedness." Antibodies 12.1 (2023): 7. https://doi.org/10.3390/antib12010007
Tornetta, Mark A., et al. "Guidelines in the Preparation of Fully Synthetic, Human Single-Domain Antibody Phage Display Libraries." Antibodies 14.3 (2025): 71. https://doi.org/10.3390/antib14030071
Distributed under Open Access license CC BY 4.0, without modification.
Please kindly note that our services can only be used to support research purposes (Not for clinical use).
Creative Biolabs is a globally recognized phage company. Creative Biolabs is committed to providing researchers with the most reliable service and the most competitive price.
Fig.1 Structural comparison: conventional IgG, scFv, and camelid VHH.1,3
Fig.2 Construction strategies for natural, semi-synthetic, and fully synthetic antibody phage libraries.2,3
