Nanobodies against lung cancer: delivering chemotherapy directly to the tumor

Signal Transduction and Targeted Therapy presented a platform for targeted therapy for lung adenocarcinoma (LUAD): the researchers created nanobodies A5 against the protein CD155 (PVR), which is overexpressed in LUAD and is associated with a worse prognosis. A5 not only firmly “sticks” to CD155 (Kd ≈ 0.23 nM), but also inhibits tumor cell migration, and when combined with liposomes with doxorubicin, it increases uptake and cytotoxicity against CD155-positive cells by 2-3 times. In mouse models and xenografts from lung tumor organoids, such a conjugate slows growth and hits the target more accurately.

Background of the study

Lung adenocarcinoma (LUAD) is the most common subtype of lung cancer and a leading cause of cancer-related death. Even in the “age of targets and immunotherapy,” a significant proportion of patients do not have driver mutations with available drugs, and those who do quickly develop resistance. PD-1/PD-L1 immunotherapy has improved outcomes, but only a minority respond, often for a short time. Therefore, new targets that simultaneously address tumor invasiveness and immune evasion are coming to the fore.

CD155 (aka PVR/Necl-5) is an immunoglobulin superfamily molecule that is frequently overexpressed by LUAD tumor cells. CD155 has a dual “role.” On the one hand, it is an immune contact hub: it binds the inhibitory receptors TIGIT and CD96 on T and NK cells (inhibiting them) and the costimulator CD226 (activating them). With excess CD155, the balance shifts toward the immune brake, which helps the tumor evade surveillance. On the other hand, CD155 is involved in adhesion and migration: via focal contacts (FAK/PXN) and the cytoskeleton, it enhances cell motility and invasion, which is clinically associated with a worse prognosis.

Against this background, the idea of a "double strike" is logical: to use CD155 both as an address for the delivery of cytostatics and as a lever to weaken migration/invasion. Classic monoclonal antibodies do not always cope with targeting: they are large, penetrate dense tumor tissue worse, and are more expensive to produce. Nanobodies (VHH) - single-domain antibodies of camels - are smaller in size (~15 kDa), more stable, simpler to construct, easier to cross-link with carriers (liposomes, nanoparticles) and diffuse better into the tumor. They can be "planted" on the surface of a liposome with doxorubicin or another "cargo", increasing the capture of CD155-high by cells.

There are also pitfalls that are important to consider in translation: CD155 is also found in normal tissues (careful toxicology and off-target assessment are needed), the short half-life of the nanobody requires prolongation of life (e.g., albumin binding/PEG modification), and the combination with immunotherapy (anti-PD-1/anti-TIGIT) needs to be tested for compatibility and synergy. Nevertheless, if addressing CD155 ensures superior drug accumulation in the tumor and simultaneously undermines migration cascades (via paxillin/focal contacts), this will provide a real chance to improve control of LUAD in places where conventional schemes have already been exhausted.

What did they do?

• Anti-CD155 nanobodies A5 (VHH, ~15 kDa) with picomolar affinity for lung tumor cells were selected and characterized.
• It was found that the A5-CD155 contact “breaks” focal contacts: the level of paxillin (PXN) decreases, which results in a >50% decrease in cell migration.
• We assembled A5-liposomes with doxorubicin (A5-LNP-DOX) and compared them with unlabeled liposomes and free A5.
• The efficacy was tested in vitro (A549/CD155high) and in vivo: orthotopic lung cancer models and xenografts from patient-derived organoids (LCO).

Key Results

• Binding: A5 is tightly bound to CD155-positive cells; the complex is stable due to hydrophobic and hydrogen bonds in the CDRs. (Kd ≈ 0.23 nM).
• Anti-migration effect: suppression of the focal adhesion cascade via PXN → >50% reduction in migration.
• Drug Delivery: A5-LNP-DOX yields 2-3× greater cellular uptake and cytotoxicity in A549 compared to control liposomes.
• Animal therapy: marked growth inhibition in orthotopic lung cancer and organoid xenografts; increased apoptosis (active caspase-3), decreased proportion of tumor tissue on histology.

Why the CD155 target is important

CD155 in the lung is not only an “immune pedal” (interacts with CD226/TIGIT/CD96), but also a participant in tumor cell adhesion and movement. In clinical data, the CD155-PXN axis correlates with survival: high levels of both proteins are associated with a worse prognosis in patients with LUAD. This makes CD155 a dual target: for drug delivery and for undermining invasiveness.

• Fact from biobanks and TMA:
  • CD155 and PXN are combined in expression in samples;
  • high PXN - shorter overall survival;
  • The combination of high CD155 + high PXN - the worst survival.

Why are nanobodies good for oncology?

• Size ~1/10 of normal IgG → better penetration into the tumor.
• Thermal stability, solubility, modular assembly for carriers (liposomes/nanoparticles).
• Production in microbial systems → cheaper and more scalable than classical antibodies.
• Nanobodies already have a clinical precedent (caplacizumab), which simplifies the path to translation in oncology.

Delivery details: how A5 “carries” doxorubicin

• A5-LNP-DOX specifically binds to CD155 on the surface of tumor cells, targeting the liposome for endocytosis.
• In A549/CD155high culture this results in a 2-3× increase in intracellular accumulation and cell death.
• In pulmonary orthotopic xenograft and LCO xenografts, the drug reduces tumor mass/volume more than unconjugated analogues, with an increase in apoptosis (caspase-3+ cells).

What does this mean "in practice"

• Potentially indicated in the future: LUAD CD155-high (with concomitant high PXN - highest risk group).
• How to use: as a targeted “chemistry” (A5-LNP-DOX) and as an anti-migration agent (blockade of the CD155-PXN axis).
• Where it might "get stuck": Soluble CD155 isoforms could theoretically "intercept" A5, but in the lines tested, the membrane variant CD155α dominated; β/γ were minimal.

Limitations and open questions

• This is preclinical work: cell models, mice, individual organoid lines (patient variability not yet covered).
• Pharmacological safety, toxicology, pharmacokinetics, and comparison with existing anti-CD155 approaches (including immunotherapy) are needed.
• Testing compatibility with immune drugs (anti-TIGIT/PD-1) and dosing regimens for better synergy.

Why is the news important?

The team shows that CD155 is not only an “immune address,” but also a convenient “handle” for precise delivery of cytostatics, with a mechanistic benefit: simultaneous disruption of migration via PXN. If the result is replicated in broader organoid panels and in GLP toxicology, high-CD155 LUADs may provide a new class of targeting conjugates that are compact, penetrating, and cost-effective to manufacture.

Source: Noh K. et al. Targeting CD155 in lung adenocarcinoma: A5 nanobody-based therapeutics for precision treatment and enhanced drug delivery. Signal Transduction and Targeted Therapy (published July 10, 2025). DOI: 10.1038/s41392-025-02301-z.