NM-02, an anti-HER2 single-domain antibody

NM-02 demonstrates how VHHs can function as molecular delivery vehicles, rather than simply as standalone therapeutic binders.

Target:

Human Epidermal Growth Factor Receptor 2 (HER2)

Why it matters:

NM-02 is an anti-HER2 single-domain antibody developed as a potential theranostic. Theranostics combines diagnosis and therapy, using the same molecular targeting strategy to first identify disease and then potentially deliver treatment.

For NM-02, the VHH provides the HER2-targeting component, while different radionuclides can provide either an imaging or therapeutic function. HER2 is a well-characterised cell-surface glycoprotein which is overexpressed in 10-30% of breast cancers, making it an important therapeutic target.

The small size and rapid pharmacokinetics of NM-02 make it particularly interesting for nuclear medicine, where rapid tumour targeting and clearance of unbound tracer can help generate useful imaging contrast while providing a potential route for targeted radionuclide delivery.

What makes it special:

• NM-02 showed high-affinity and highly specific binding to HER2.
• Its structure in complex with HER2 has been solved, showing how this VHH recognises its target.
• NM-02 recognises an epitope that does not overlap with those of current frontline treatment options (Trastuzumab and Pertuzumab). This is a good example of the epitope diversity accessible with VHHs.
• Radionuclide versatility: NM-02 has been investigated with radionuclides for both HER2 imaging and targeted radionuclide therapy.

Big impact:

NM-02 demonstrates how VHHs can function as molecular delivery vehicles, rather than simply as standalone therapeutic binders. The VHH acts as the targeting molecular which recognises HER2 and carries a radioactive payload to HER2-expressing tissue. By changing the radionuclide, the same targeting principle can potentially be used for either imaging or therapy.

This concept has reached clinical investigation. NM-02 has been radiolabelled with ^99mTc (an imaging radionuclide) and clinically investigated for SPECT/CT imaging of HER2 expression in breast cancer. The clinical study NCT04674722 also included ^188Re-NM-02, in which NM-02 carries a therapeutic radionuclide for targeted radionuclide therapy.

Overall, NM-02 is part of a broader effort to translate HER2-targeting VHHs into the clinic. Other examples include 2Rs15d, which has been investigated for both HER2 imaging and targeted radionuclide therapy, as well as MIRC208 and MIRC213, which have entered clinical studies as HER2 imaging agents. Despite the CAM-H2 study based on the 2Rs15d anti-HER2 VHH being terminated following a strategic decision by the trial sponsor, together these and other programmes highlight growing interest in VHHs as targeting molecules for molecular imaging and radionuclide delivery.

Cool fact:

• NM-02 provides a good opportunity to visualise VHH targeting at two completely different scales.
• At the molecular level, PDB 7QVK shows NM-02 physically bound to HER2.
• At the whole-body level, radiolabelled NM-02 has been used clinically to visualise HER2-expressing lesions using SPECT/CT.

References:

Sawmynaden K, Wong N, Davies S, et al.
Co-crystallisation and humanisation of an anti-HER2 single-domain antibody as a theranostic tool. PLOS ONE. 2023; 8(7), e0288259. doi:10.1371/journal.pone.0288259.

Zhao L, Xing Y, Liu C, et al. (2024).
Detection of HER2 expression using ^99mTc-NM-02 nanobody in patients with breast cancer: a non-randomized, non-blinded clinical trial. Breast Cancer Research. 2024;26, 40. doi:10.1186/s13058-024-01803-y.

ClinicalTrials.gov — NCT04674722. Technetium-99m/Rhenium-188 Labeled Anti-HER2 Single Domain Antibody (99mTc/188Re-NM-02) for HER2 Expression Detection and Radionuclide Therapy in Breast Cancer. Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine. Early Phase 1; completed; 43 participants.

Sawmynaden et al. NM-02 in complex with HER2-ECD. 2023;PDB ID: 7QVK. Image adapted from RCSB PDB (RCSB.org).

Sawmynaden K, Wong N, Davies S, et al. Co-crystallisation and humanisation of an anti-HER2 single-domain antibody as a theranostic tool. PLoS One. 2023;18:e0288259. doi:10.1371/journal.pone.0288259.