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Anti-HER2 VHH

Anti-HER2 VHH

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Anti-HER2 VHH

There are many factors associated with a more aggressive tumor subtype and poorer prognosis, such as the overexpression of human epidermal growth factor 2 (HER2). Given that, how HER2-targeted radiotracers develop is essential for the non-invasive in vivo diagnosis of HER2-positive tumors. And antibodies may be the best answer.

Among the antibodies, nanobodies, also known as Heavy-Chain Variable (VHH) or Single Domain Antibody (SdAb), gain special attention due to their favorable kinetics. Nanobodies are capable of penetrating tumor tissues and binding highly specifically to antigens with small size and high affinity. All these make nanobodies a suitable treatment and diagnostic aid.

Numbers of candidates, such as 2Rs15d, NM-02, 5F7, MIRC208, MIRC213, 11A4, 18C3, 22G12, are undergoing preclinical and clinical studies.

The reason to select 2Rs15d (anti-HER2-VHH1) as the lead compound lies in its overall optimal properties of high affinity and in vivo tumor targeting, as well as its non-competitive property with trastuzumab and pertuzumab in HER2 targeting. And 2Rs15d has demonstrated excellent targeting of HER2 both in preclinical and clinical trials.

A phase I trial of 68Ga-labeled 2Rs15d suggests that 68Ga-NOTA-2Rs15d may be suitable for assessing HER2 expression in metastatic lesions, but not in primary BC lesions. Currently, two phase II studies of 2Rs15d are undergoing, including a phase II trial (NCT03331601) evaluating its potential for evaluating brain metastases of BC, and a phase II clinical study (NCT03924466) evaluating the association between image-based HER2 positive tumor quantification and uptake of 68Ga-NOTA-2Rs15d in local or distant metastatic focal in BC patients.

NanoMab developed another anti-HER2 sdAb, named NM-02. It is shown that 99mTc labeled NM-02 performed safety and tumor targeting potential in 10 BC patients in its first human trial (NCT04040686). In addition, another phase I trial (NCT04674722) is underway, for noninvasive diagnosis and radionuclide-targeted treatment for HER2 positive breast cancer.

Ablynx (now part of Sanofi) developed Radiolabeled 5F7, which has maintained excellent affinity and immunoreactivity after radiolabeling in preclinical trials. Moreover, PET imaging based on 68Ga/131I SGMIB-labelled 5F7 for the diagnosis of HER2-positive metastatic breast cancer is under investigation.

Yaohai Bio-Pharma Offers One-Stop CDMO Solution for VHH/ sdAb
Anti-HER2 VHH In Development
Anti-HER2 VHH Expression System Radiolabel Stage Clinical Trials
2Rs15d Escherichia coli (E. coli) WK6 68Ga Phase 2 NCT03331601
Phase 2 NCT03924466
other labels preclinical NA
NM-02 E. coli BLR (DE3) 99mTc Phase 1 NCT04040686
Phase 1 NCT04674722
other labels preclinical NA
5F7 E. coli 68Ga Phase 1 NCT05982626
131I Phase 1 NCT05982626
other labels preclinical NA
MIRC208 E. coli 99mTc First-in human NCT04591652
MIRC213 E. coli 99mTc Phase 1 NCT05622240
11A4 E. coli IRDye 800CW preclinical NA
18C3 E. coli IRDye 800CW preclinical NA
22G12 E. coli IRDye 800CW preclinical NA
VHH_1028 E. coli 131I preclinical NA
Reference:

[1] Ge S, Li J, Yu Y, Chen Z, Yang Y, Zhu L, Sang S, Deng S. Review: Radionuclide Molecular Imaging Targeting HER2 in Breast Cancer with a Focus on Molecular Probes into Clinical Trials and Small Peptides. Molecules. 2021 Oct 27;26(21):6482. doi: 10.3390/molecules26216482.

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