Biologic therapies have reshaped oncology, but they come with real limitations. Traditional monoclonal antibodies are large, complex molecules that can struggle with tumor penetration, slow development timelines, and costly manufacturing. In a field where time is critical and healthcare budgets are under increasing pressure, these constraints can hold back promising innovations.

VHH antibodies, also known as nanobodies or single-domain antibodies, offer a practical alternative. At just ~15 kDa, they’re a fraction of the size of conventional antibodies, yet maintain strong affinity, high specificity, and low immunogenicity. Their compact format allows for better tumor access and greater format flexibility.

At Isogenica, we focus on advancing this potential. Our synthetic VHH libraries are designed to streamline antibody discovery and help address some of the key challenges in oncology R&D. As interest in smaller, more versatile antibody formats grows, VHHs are emerging as a valuable tool for teams looking to improve efficiency and opening new possibilities in drug discovery.

The challenge for conventional antibodies

Monoclonal antibodies have been a cornerstone of cancer therapy for decades, but they come with inherent limitations. Their large size hampers uniform diffusion through solid tumor masses, and it’s common for antibodies to penetrate deeper tumor regions poorly, leaving pockets of untreated tissue behind [1].

Tumor heterogeneity, combined with the molecular weight of a conventional IgG, result in uneven distribution within the tissue, contributing to suboptimal therapeutic responses [1]. Moreover, the development of traditional antibodies is complex and resource intensive. The process typically involves animal immunization, hybridoma generation or B-cell selection, followed by expression in mammalian cell lines. This entails high costs, extended R&D timelines, and challenges in scaling up production [2].

Additionally, their biophysical stability is often limited: many immunoglobulins lose activity outside narrow temperature and pH ranges, require constant refrigeration, and may aggregate or degrade over time. These issues of stability, manufacturability, and tumor penetration drive the need for more robust alternatives.

VHH antibodies: small but mighty

In response to the challenges posed by conventional antibodies, VHH antibodies present an innovative and powerful solution. Comprising only the variable domain of a heavy chain only antibody, VHHs retain high antigen-binding affinity while offering a more streamlined, robust and versatile format. These are the smallest known antigen-binding molecules in nature, capable of recognizing targets with high specificity [3]. These properties translate to key advantages of VHH antibodies in oncology: 

Extraordinary Stability. VHHs maintain their structure and function under harsh conditions that would inactivate many conventional antibodies. They can tolerate heat, acidic pH, and proteolytic environments, thanks to their compact structure and single disulfide bond that enhances stability [4]. Some VHHs remain active for days at body temperature and even after exposure to gastrointestinal extracts, broadening formulation and administration possibilities (IV, oral, inhaled), while reducing degradation issues during storage or transport [1]. 

Simplified and cost-effective manufacturing. Due to their small size and simple structure, VHHs can be expressed efficiently in microbial systems like bacteria or yeast, unlike full-length IgGs, which require more resource-intensive mammalian cell culture due to their requirement for species-matched glycosylation. This means faster R&D, as well as manufacturing at a fraction of the cost [2]. 

Enhanced tumor penetration. VHHs diffuse more easily and evenly through tumor tissue, due to their size – 10 times smaller than an IgG. This enhanced penetration allows them to reach target cells in tumor niches inaccessible to larger molecules. Preclinical studies have demonstrated this benefit: an anti-PD-L1 VHH, for instance, showed greater tumor growth inhibition in mice than its conventional counterpart, due to deeper and more homogeneous tumor penetration [1]. Some VHHs have even been reported to cross the blood-brain barrier—or be engineered to do so—opening the door to brain tumor therapies beyond the reach of standard antibodies [5]. 

Improved Pharmacokinetics for Radioimaging. In oncology treatment, diagnosis can be as important as treatment. Advances in molecular imaging techniques have exploited the short half life of unmodified VHH antibodies (often ~30 minutes) to allow for precise imaging of antigen-expressing tumors while minimizing toxicity from the radionuclide. For other applications, VHHs can be modified in numerous ways to extend half-life out to weeks at a time, as it is explained in this blog [6]. 

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Targeting hard-to-reach epitopes and modular engineering. VHHs typically feature longer, flexible CDR3 loops, enabling them to reach antigen pockets or enzymatic clefts that are inaccessible to larger antibodies [1]. This flexibility expands the scope of druggable cancer targets. Structurally, they are easy to engineer into multi-specific formats: two or more VHHs can be linked to create bi- or tri-specific molecules that engage multiple antigens at once [4].

VHHs present a new frontier in oncology, combining exceptional stability, targeted efficacy, and scalability, making them a powerful alternative to conventional antibodies. Their unique properties offer vast potential for improving cancer treatment outcomes while overcoming many of the limitations associated with traditional antibody-based therapies.

Application Example – VHH antibodies to build new therapies in oncology 

Although VHHs are a relatively new technology, they have already made a significant impact in oncology. In 2021, envafolimab (KN035) became the first VHH-based immune checkpoint inhibitor approved in China, targeting PD-L1 in patients with MSI-H (microsatellite instability-high) advanced solid tumors [4]. This humanized VHH-Fc fusion showed comparable efficacy and safety to other PD-L1 antibodies, with one clear advantage:  it is the first to enable subcutaneous dosing, administering a full dose in 30 seconds. The rapid delivery opens the way to home treatment, putting an end to the necessity of hospital-based infusion and creating significant cost savings in healthcare systems. Phase I/II trials confirmed sustained therapeutic levels and promising antitumor activity, validating both the clinical potential of VHHs and the benefits of simpler delivery [7]. 

Another success story is Carvykti® or ciltacabtagene autoleucel (cilta-cel), a CAR-T cell therapy approved by the FDA in 2022 for relapsed or refractory multiple myeloma. In this personalized cell therapy, a patient’s T cells are engineered to express a chimeric antigen receptor (CAR) whose antigen-recognition domain consists of two VHHs targeting different places on the BCMA antigen on myeloma cells [4]. This approach has shown unprecedented deep response rates in patients with heavily pretreated multiple myeloma. The choice of VHHs over conventional scFv fragments was based, among other factors, on their smaller gene length, allowing a more highly functional bi-paratopic construct to be encoded in the same space as just one scFv. 

This expanding landscape reflects growing confidence in VHHs’ ability to target difficult cancer epitopes (e.g., tumor microenvironment receptors, soluble ligands) through novel strategies—whether as single-domain antibody-drug conjugates, bi-specific constructs, or delivery vehicles for toxins and radionuclides directly to tumors. 

Faster VHH discovery with Isogenica 

A key advantage of Isogenica’s VHH technology for biotech companies is its ability to significantly accelerate drug discovery and development. Instead of waiting months for animal immunization, researchers can screen the largest synthetic VHH libraries on the market to identify hits in just weeks via in vitro panning. This faster, animal-free process also allows assessment of multiple target types in parallel – ideal for challenging targets such as membrane proteins. 

Working with the VHH format also allows us to accelerate early-stage R&D. High-throughput E. coli expression systems integrate seamlessly with automated liquid handling, which allows thousands of sequence-function relationships to be assessed per day. In parallel, deep sequencing analysis can be run as a complementary activity identify rare binders and critical paratope regions. Together, both approaches provide a comprehensive view of these high-diversity selection outputs, which are unaffected by bias from animal immune systems.  

Conclusion 

The emergence of VHH antibodies in oncology is revolutionizing antibody-based therapies by allowing the development of more functionally complex therapies using these versatile building blocks. These small yet powerful molecules combine the specificity of traditional antibodies with enhanced stability, versatility in different therapeutic formats, and faster development timelines. Recent success stories — from subcutaneously administered immune checkpoint inhibitors to CAR-T therapies using tandem VHH domains — show that these small but mighty antibodies have evolved from scientific curiosities into clinically relevant tools. 

With many candidates in clinical trials and growing momentum behind the science, VHH antibodies are positioned to lead the next wave of precision cancer therapies. Their size, stability, and engineering potential offer a smarter, faster way to reach challenging targets. 

Curious about how VHHs could accelerate your oncology pipeline? Explore our latest research and insights on VHH-based therapies. 

References 

[1] Cong, Y., Devoogdt, N., Lambin, P., Dubois, L. J., & Yaromina, A. (2024). Promising Diagnostic and Therapeutic Approaches Based on VHHs for Cancer Management. Cancers, 16(2), 371. https://doi.org/10.3390/cancers16020371 

[2] Fortis Life Sciences. (2025). Beyond mAbs: The unrealized potential of VHH antibodies. https://www.fortislife.com/resources/antibody-resources/beyond-mabs-the-unrealized-potential-of-vhh-antibodies 

[3] Ortega-Monge, C., Arce-Rodríguez, N., Santamaría-Muñoz, M., Chavarria-Rojas, M., Rojas Salas, M. F., Baltodano Viales, E., & Madrigal Redondo, G. L. (2022). Aplicaciones de los nanoanticuerpos en la medicina. Ars Pharmaceutica, 63(2), 125–137. https://dx.doi.org/10.30827/ars.v63i2.22199 

[4] Biopharma PEG. (2023, October 25). Nanobodies – Current status and prospects. https://www.biochempeg.com/article/375.html 

[5] Medina Pérez, V. M., Baselga, M., & Schuhmacher, A. J. (2024). Single-Domain Antibodies as Antibody–Drug Conjugates: From Promise to Practice—A Systematic Review. Cancers, 16(15), 2681. https://doi.org/10.3390/cancers16152681 

[6] https://isogenica.com/half-life-extension/ 

[7] Alphamab Oncology. (n.d.). Envafolimab (KN035). Retrieved April 11, 2025, from https://www.alphamabonc.com/en/pipeline/kn035.html