Discover how ancient immune proteins from jawless vertebrates are revolutionizing modern medicine
Explore the ScienceImagine if the key to developing next-generation medical treatments wasn't found in human laboratories, but in the ancient immune systems of one of Earth's most primitive vertebrates. Variable Lymphocyte Receptors (VLRs)—the unique antibody alternatives used by jawless vertebrates like lampreys and hagfish—are revolutionizing how scientists approach disease detection, drug delivery, and therapeutic development.
These extraordinary proteins can target everything from viral particles to cancer cells with precision, often recognizing molecules that conventional antibodies cannot. As research progresses, VLRs are emerging as powerful tools in the fight against some of medicine's most persistent challenges, from brain disorders to HIV and cancer.
Jawless vertebrates (lampreys and hagfish) represent an ancient evolutionary lineage that diverged from jawed vertebrates approximately 500 million years ago. Despite lacking conventional antibodies, these creatures possess a sophisticated adaptive immune system centered around VLRs 5 8 .
Structural Insight: Unlike immunoglobulins, which use the immunoglobulin fold, VLRs are built from leucine-rich repeat (LRR) modules—the same structural motif found in Toll-like receptors and many other pathogen-sensing proteins 6 .
The exceptional capabilities of VLRs stem from their unique structural design, which differs dramatically from conventional antibodies.
VLRs achieve their remarkable diversity through a gene conversion-like process. In the germline, VLR genes are incomplete, consisting of framework sequences flanked by hundreds of diverse LRR cassettes. Through somatic assembly, these cassettes are randomly inserted to create mature, functional VLR genes 3 .
This assembly mechanism generates a theoretical diversity exceeding 10¹⁴ unique receptors—rivaling the diversity of mammalian antibody repertoires 3 .
Mature VLR proteins form a characteristic horseshoe-shaped solenoid structure (curved, spring-like shape) 1 6 . The concave surface, formed by parallel β-sheets from the LRR modules, serves as the primary antigen-binding site. Within this binding interface, highly variable residues create specificity for different antigens, while a flexible, variable-length insert in the LRRCT module further contributes to antigen recognition 1 6 .
| Feature | Conventional Antibodies | VLRs |
|---|---|---|
| Basic structural unit | Immunoglobulin fold | Leucine-rich repeats |
| Structure | Y-shaped | Horseshoe/solenoid-shaped |
| Binding interface | Formed by highly variable loops (CDRs) | Concave β-sheet surface + variable CT loop |
| Diversity generation | V(D)J recombination + somatic hypermutation | Combinatorial LRR module assembly |
| Subunit composition | Paired heavy and light chains | Single polypeptide chain |
| Natural form | Typically monomers or dimers | Often form multimers (octamers/decamers) |
| Reagent/Resource | Primary Function | Application Examples |
|---|---|---|
| Immune VLR libraries | Source of antigen-specific VLRs | Generated from immunized lampreys; used for screening binders against various antigens 3 |
| Non-immune VLR libraries | Source of naive VLR repertoire | Contain natural VLR diversity (~10¹⁴ clones) for in vitro screening 6 |
| Designed VLR scaffolds (dVLR, repebody) | Engineered consensus scaffolds | Stable frameworks for library construction and engineering 6 |
| Yeast surface display | VLR screening platform | Display VLRs on yeast surface for affinity-based selection 9 |
| Phage display | Alternative display platform | VLR library screening using bacteriophage 6 |
| Long-read sequencing (PacBio) | VLR repertoire analysis | Full-length VLR sequencing despite variable transcript lengths 5 8 |
One particularly promising application of VLR technology involves overcoming one of medicine's greatest challenges: delivering therapeutics across the blood-brain barrier (BBB). A groundbreaking study published in 2025 demonstrated the power of VLRs to identify novel human-relevant BBB targets 9 .
The research team employed an innovative screening strategy:
Three sea lampreys were immunized with fixed human-induced pluripotent stem cell-derived brain microvascular endothelial-like cells (iPSC-derived BMEC-like cells), which closely mimic the human BBB 9 .
VLRB cDNA was amplified from lamprey lymphocytes and cloned into yeast surface display vectors, creating a diverse library of potential BBB-binding VLRs 9 .
The yeast-displayed VLR library was screened against human iPSC-derived BMEC-like cells to isolate specific binders 9 .
Lead VLR candidates were tested across multiple models: binding to human and mouse brain tissue sections, functionality in human in vitro BBB models, and brain uptake capability in live mice 9 .
The most promising candidate, VLR2G, was conjugated to the neuroactive peptide neurotensin and administered intravenously to mice to assess its ability to deliver functional payloads across the BBB 9 .
The study yielded compelling results:
From the immune library, researchers identified 15 lead VLR candidates
14 of these VLRs bound to human BBB antigens, demonstrating high targeting success
10 VLRs cross-reacted with the murine BBB, enabling preclinical testing in mouse models
Most significantly, VLR2G successfully delivered neurotensin across the BBB in mice, producing a measurable physiological response (lowered body temperature) 9
| Advantage | Explanation | Impact |
|---|---|---|
| Evolutionary distance | Lampreys lack tolerance to human antigens | Enables recognition of conserved epitopes that mammalian antibodies might ignore 6 |
| Structural uniqueness | Concave binding surface differs from flat antibody partatopes | Better suited for binding certain glycan and protein configurations 3 |
| Phenotypic screening | Can identify targets without prior molecular knowledge | Discovers novel receptors and biomarkers 9 |
| Human relevance | Immunization with human cells yields human-specific binders | Overcomes species translation challenges 9 |
The utility of VLR technology extends far beyond BBB targeting, with active research across multiple biomedical domains.
VLRs show particular promise in oncology, where they can target tumor-associated carbohydrates and proteins that often evade conventional antibody detection. Their unique structural properties enable recognition of structurally cryptic epitopes on cancer cells, making them valuable tools for both diagnosis and targeted drug delivery 3 .
VLRs have been successfully developed against various pathogens, including:
In some cases, VLRs demonstrate exceptional specificity, such as distinguishing between closely related bacterial surface proteins with 89.5% sequence identity 6 .
The small size and stability of monomeric VLRs make them ideal candidates for molecular imaging applications. Engineered VLRs can be developed into sensitive detection reagents for conditions ranging from infectious diseases like malaria to cancer biomarker identification 3 .
Variable Lymphocyte Receptors represent more than just a biological curiosity—they offer a powerful and versatile platform for addressing longstanding challenges in therapeutics and diagnostics. As research progresses, we can anticipate seeing more VLR-based tools transition from laboratory curiosities to clinical applications.
The unique structural properties of VLRs, combined with their ability to recognize challenging epitopes, position them as valuable complements to traditional antibodies. From enabling targeted drug delivery across the blood-brain barrier to improving cancer detection and treatment, these ancient immune proteins are poised to make a significant impact on modern medicine. As one researcher aptly noted, VLRs have evolved "from an immunological curiosity into a powerful platform for molecular recognition and biomedical application" 3 .
The continued exploration of VLR biology and technology stands to benefit multiple fields, offering new hope for treating some of medicine's most formidable diseases. In the primitive immune system of the lamprey, we may have found unexpected solutions to some of our most advanced medical challenges.