June 26, 2022

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Clinical Application of Nanobodies in Six Major Tumors

Clinical Application of Nanobodies in Six Major Tumors



Clinical Application of Nanobodies in Six Major Tumors.

Traditional antibodies have a molecular weight of about 150KD and a size of 14.2 nm × 8.2 nm × 3.8 nm, which makes the penetration of solid tumors poor and the curative effect of solid tumors is not ideal.

Nanobodies (heavy chain variable region VHH) from camelids and sharks have a molecular weight of about one-tenth of that of traditional antibodies, giving people hope for the treatment of solid tumors.

This article summarizes the eight advantages of Nanobodies and their six applications in clinical tumor diagnosis.

Clinical Application of Nanobodies in Six Major Tumors


Advantages of Nanobodies

The molecule 1 is small. The molecular weight of 12-14KD is about one-tenth that of traditional antibodies.

1. Low immunogenicity. The sequences of Nanobody and human IgG heavy chain are more than 80% identical, and the molecular weight is small, so the immunogenicity is weak, and the production of anti-drug antibodies is less. Helps avoid the problem of drug resistance caused by repeated medications.

2. High stability.

3. High degradation resistance. It can withstand changes in temperature, pressure and pH, and is easy to store and transport.

4. Prokaryotic expression.

5. Low mass production cost.

6. Good tissue penetration, suitable for imaging diagnosis and treatment of solid tumors.

7. Product characterization is easy. The structure is simple, the post-translational modification is low, and the homogeneity is good.


Six applications of Nanobodies

Molecular imaging

Cancer can be visualized by single photon emission computed tomography (SPECT), positron emission tomography (PET), computed tomography (CT), ultrasound and optical imaging.

Antibodies and nanobodies are linked to radionuclides, positron emitting radioisotopes and near-infrared fluorophores. Radionuclides (99mTc, 177Lu, 123I, etc.) are used for SPECT imaging, while positron emitting radioisotopes (68Ga, 124I, 89Zr, 18F, etc.) are used for PET imaging.

Because of its small molecular weight and good tissue penetration, Nanobodies have fast imaging time (1-3 hours), rapid clearance in the body, and higher tumor/background ratio. They are better imaging antibodies than traditional monoclonal antibodies.

Clinical Application of Nanobodies in Six Major Tumors

Molecular imaging is widely used in: target distribution, antibody drug distribution in vivo, tumor diagnosis and other fields.

Tumor diagnosis

Combining a therapeutic compound with a diagnostic radiotracer and performing a diagnostic scan can visualize the accumulation of the compound in cancer cells. Radiolabeled Nanobodies can be used to identify specific tumor-related biomarkers, thereby helping cancer diagnosis and determining appropriate treatment methods.

Nanobodies diffuse rapidly into tissues and accumulate specifically in target tissues (with minimal accumulation in non-target tissues), which results in the rapid generation of high-contrast images, allowing early diagnosis of patients. Radiolabeled Nanobodies can be used for whole body scans to detect the distribution of primary tumors and metastatic lesions (as shown below).

Clinical Application of Nanobodies in Six Major Tumors

Diagnostic scans are helpful in estimating dose, monitoring treatment response, evaluating treatment efficiency and predicting adverse effects of treatment.

Imaging guided surgery

The vast majority of tumors require surgical treatment, and by 2030, 45 million operations may be required a year globally. The purpose of preventive surgery is to remove cancer-prone tissues, with less damage, lower cost, and minimize malignant lesions. Diagnostic techniques are important for determining appropriate treatment and management of cancer.

A promising application of Nanobodies in surgery is imaging-guided surgery. A mouse human xenograft breast cancer model that combines anti-HER-2Nb (11A4) with IRDye800CW. Compared with trastuzumab-IRDye800CW, 11A4-IRDye800CW increases tumor accumulation and tumor-to-background ratio (Figure below, literature) 3). And based on image-guided surgery to remove mouse SKBR3 tumors.

Clinical Application of Nanobodies in Six Major Tumors

Targeted radiotherapy

Radiotherapy is still one of the most cost-effective treatments for tumors. About 50% of cancer patients receive radiotherapy.

The purpose of radiotherapy is to expose malignant cells to the maximum radiation dose while exposing normal cells to the minimum radiation dose. Radiation damages DNA, which may block cell proliferation and induce cell death. Healthy cells can repair themselves quickly, survive and function normally.

Radiotherapy is usually combined with chemotherapy, surgery, and immunotherapy. Although radiotherapy is beneficial, it also has some side effects, such as oral mucositis, liver toxicity, and nephrotoxicity

Targeted radionuclide therapy (TRNT) can be used to deliver radiation to malignant cells with minimal impact on healthy cells. There are two types of TRNT drugs: 1. Iodine-131 and strontium-89 that naturally accumulate in malignant tissues, and 2. TRNT drugs that target tumor-associated antigens expressed on the surface of cells.

Nanobodies have good tissue penetrability, and mark reflective nuclides to target tumor-associated antigens to achieve targeted reflex therapy. Now there are some animal model studies, showing good results.

There is a clinical trial registration (NCT03956615), but it has not yet been applied for.

HER2 single domain antibody labeled 213Bi targeted radiotherapy (Mol. Pharm. 2020, 17, 3553-3566.)

Delivery of chemotherapeutic drugs

Antibody-conjugated drugs take advantage of the specific targeting function of antibodies to carry cytotoxic drugs to the tumor. Traditional antibodies contain the Fc segment, which causes additional immunotoxicity and metabolic abnormalities due to the binding of Fc and receptors. Nanobodies do not contain Fc segment and have good tissue penetration.

Theoretically, they can reduce the occurrence of additional side effects and increase local tumor drugs, thereby reducing the systemic dosage of antibody Eurolink drugs and increasing the therapeutic index.

Nanobodies can also be used to encapsulate drugs, and can also improve solubility, stability and clearance.

Several possible forms of nanobodies as drug delivery vehicles

Immunity therapy

Tumor immunotherapy has a history of 100 years, including vaccines, cytokines, antibody drugs, immune checkpoint inhibitors, cell therapy and other technologies.

Nanobodies have higher penetration for solid tumors due to their small molecular weight. Nanobodies with the same target may produce better therapeutic effects than traditional antibodies.


Summary

Nanobodies have attracted wide attention because of their small molecular weight and good tissue penetration; they can be expressed in prokaryotic cells with low cost; they are stable in structure and easy to transport.

There are already some clinical trials of nanobodies used in imaging diagnosis, surgical treatment, immunotherapy and other fields.

References:

1. Ivana Jovčevska et al, The Therapeutic Potential of Nanobodies, BioDrugs. 2020 Feb;34(1):11-26.

2. Yan Xing et al, Early Phase I Study of a 99mTc-Labeled Anti-Programmed Death Ligand-1 (PD-L1) Single-Domain Antibody in SPECT/CT Assessment of PD-L1 Expression in Non-Small Cell Lung Cancer, J Nucl Med 2019; 60:1213–1220

3.D’Huyvetter, M.; Xavier, C.; Caveliers, V.; Lahoutte, T.; Muyldermans, S.; Devoogdt, N. Radiolabeled nanobodies as theranostic tools in targeted radionuclide therapy of cancer. Expert Opin. Drug Deliv . 2014, 11, 1939–1954

4.Dekempeneer, Y.; Caveliers, V.; Ooms, M.; Maertens, D.; Gysemans, M.; Lahoutte, T.; Xavier, C.; Lecocq, Q.; Maes, K.; Covens, P .; et al. Therapeutic Efficacy of 213Bi-labeled sdAbs in a Preclinical Model of Ovarian Cancer. Mol. Pharm. 2020, 17, 3553–3566.

5.Rosenfeld, L.; Sananes, A.; Zur, Y.; Cohen, S.; Dhara, K.; Gelkop, S.; Ben Zeev, E.; Shahar, A.; Lobel, L.; Akabayov, B.; et al. Nanobodies Targeting Prostate-Specific Membrane Antigen for the Imaging and Therapy of Prostate Cancer. J. Med. Chem. 2020, 63, 7601–7615

6.Zhang, F.; Wei, H.; Wang, X.; Bai, Y.; Wang, P.; Wu, J.; Jiang, X.; Wang, Y.; Cai, H.; Xu, T .; et al. Structural basis of a novel PD-L1 nanobody for immune checkpoint blockade. Cell Discov. 2017, 3, 17004

7.Naidoo, D.B.; Chuturgoon, A.A. Nanobodies Enhancing Cancer Visualization, Diagnosis and Therapeutics. Int. J. Mol. Sci. 2021, 22, 9778.

Clinical Application of Nanobodies in Six Major Tumors

(source:internet, reference only)


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