Week 4, November 2025: From Eggs to Sharks: How Non-Canonical Antibodies Are Reshaping Antiviral Immunotherapy

As viral threats continue to emerge and evolve, a new generation of antibody formats, derived from birds, camelids, and sharks, is gaining traction as a promising alternative for rapid, scalable, and resilient immunotherapies.

A recent review by Basabrain & Alandijany (2025) describes how avian immunoglobulin Y (IgY), camelid nanobodies (VHH), and shark variable new antigen receptors (VNARs) can exhibit unique structural and biophysical features that make them well-suited to neutralizing respiratory pathogens, particularly when delivered intranasally or via inhalable formulations.

IgY Antibodies

IgY antibodies, derived from the egg yolks of immunized birds, represent a scalable and ethical alternative to mammalian IgG. Unlike IgG, IgY lacks the Fc region that binds mammalian Fc receptors or activates complement, making it less inflammatory. Structurally, IgY demonstrates greater thermal and protease stability.

IgY has shown potent preclinical efficacy against various respiratory viruses, including influenza subtypes, SARS-CoV, and SARS-CoV-2. Intranasal administration of anti-SARS-CoV-2 IgY reduced viral load and pathology in murine models. Its production is non-invasive and cost-effective: a single hen can yield several grams of antigen-specific IgY annually without the need for blood collection. Furthermore, IgY has demonstrated high oral and nasal bioavailability in formulations such as lyophilized powders and nanoparticle-encapsulated aerosols.

Camelid VHH Antibodies (Nanobodies)

Camelid-derived nanobodies, or VHHs, are the smallest naturally occurring antibody fragments capable of antigen binding. Their compact size (~15 kDa), monomeric structure, and extended complementarity-determining region 3 (CDR3) allow them to access cryptic or recessed viral epitopes that are often hidden from conventional antibodies.

These properties have enabled nanobodies to neutralize a broad spectrum of respiratory viruses. VHH constructs targeting the hemagglutinin (HA) stem of influenza virus have demonstrated cross-subtype protection. Against SARS-CoV-2, engineered multivalent or biparatopic nanobodies have blocked receptor binding and destabilized the spike trimer, with potent activity against variants including Omicron. Importantly, their resilience under heat, pH extremes, and aerosolization makes them ideal for nasal or inhaled delivery.

A recent review highlights the wide range of engineering options for nanobody optimization. VHHs can be multimerized for avidity, humanized for reduced immunogenicity, or fused with effector domains to elicit desired pharmacokinetics or immune functions. According to structural analyses, VHHs tolerate extensive framework grafting and loop mutations, supporting their use in modular or bispecific formats.

Clinically, caplacizumab (an anti-von Willebrand factor nanobody) tis the first VHH-based biologic approved for therapeutic use, validating their safety and manufacturability. Dozens of VHH programs targeting infectious diseases are in clinical development, and at least two (ALX-0171 and VHH-72-Fc) have advanced into human trials for respiratory syncytial virus and SARS-CoV-2, respectively. These efforts benefit from robust microbial expression systems, well-characterized developability profiles, and a growing regulatory framework for single-domain biologics.

Shark VNARs

Shark-derived VNARs, the smallest known antigen-binding domains (~12 kDa), exhibit exceptional stability and binding versatility. They are made up of a single variable domain stabilized by inter-CDR disulfide bonds, which allows for recognition of highly conserved, often recessed viral epitopes. VNARs have demonstrated promising preclinical efficacy against influenza and SARS-CoV-2. For instance, VNARs targeting the influenza M2 ion channel retained neutralizing activity even in amantadine-resistant strains. Recent studies have identified VNARs capable of cross-neutralizing SARS-CoV-1, SARS-CoV-2 variants, and other zoonotic coronaviruses by targeting conserved regions outside the ACE2-binding site. Engineered Fc-fusion VNARs delivered intranasally significantly reduced lung viral loads in infected mice.

A Shift Toward Modular, Variant-Resilient Biologics

The modularity of nanobodies and VNARs supports the development of multivalent, bispecific, or trispecific constructs that can simultaneously target distinct viral epitopes. This engineering flexibility is critical in the face of viral antigenic drift, as seen with SARS-CoV-2 and influenza. By engaging multiple conserved epitopes, these constructs reduce the likelihood of immune escape.

Moreover, the combination of high stability, deep-tissue penetration, and mucosal compatibility positions non-canonical antibodies for field-deployable use in outpatient and low-resource settings. Inhalable or intranasal formulations that bypass cold-chain storage could offer rapid protection during pandemics, even before vaccines are available.

Despite their promise, non-canonical antibody formats face several challenges. Their small size leads to rapid renal clearance, requiring half-life extension strategies. Shark VNARs may pose immunogenicity risks due to their phylogenetic distance from humans. Furthermore, manufacturing pipelines and regulatory pathways tailored to these platforms remain underdeveloped.

However, advances in Fc engineering, PEGylation, and synthetic library selection are rapidly addressing these limitations. With increasing preclinical and early clinical evidence, regulatory momentum is beginning to shift. The unique properties of IgY, nanobodies, and VNARs justify their inclusion in pandemic-preparedness frameworks and broader antiviral portfolios.