PurposeThe unique structure of nanobodies is advantageous for the development of radiopharmaceuticals for nuclear medicine. Nanobodies targeted to human epidermal growth factor receptor 2 (HER2) can be used as tools for the imaging and therapy of HER2-overexpressing tumors. In this study, we aimed to describe the generation of a ¹³¹I-labeled anti-HER2 nanobody as a targeted radionuclide therapy (TRNT) agent for HER2-positive breast cancer.MethodsThe anti-HER2 nanobody NM-02 was labeled with ¹³¹I using the iodogen method, and its radiochemical purity and stability in vitro were assessed. The pharmacokinetic profile of ¹³¹I-NM-02 was investigated in normal mice. Tumor accumulation, biodistribution, and therapeutic potential of ¹³¹I-NM-02 were evaluated in HER2-positive SKBR3 xenografts; HER2-negative MB-MDA-231 xenografts were used as the control group.Results¹³¹I-NM-02 could be readily prepared with satisfactory radiochemical purity and stability in vitro. Apparent tumor uptake was observed in HER2-positive tumor-bearing mice with rapid blood clearance and favorable biodistribution. ¹³¹I-NM-02 could significantly inhibit tumor growth and extend the life of these mice with good organ compatibility. Negligible tumor accumulation and inhibitory effects of ¹³¹I-NM-02 were observed in the negative control group.Conclusion¹³¹I-NM-02 has the potential to be explored as a novel tool for TRNT of HER2-positive breast cancer.

01 Jul 2021·International Journal of Biological MacromoleculesQ1 · CHEMISTRY

An anti-HER2 nanobody binds to its antigen HER2 via two independent paratopes

Q1 · CHEMISTRY

Article

Author: Grandori, Rita ; Iacobucci, Claudio ; Sinz, Andrea ; Kovačič, Matic ; Oloketuyi, Sandra ; Bajc, Gregor ; Ubbiali, Daniele ; Medagli, Barbara ; Semrau, Marta S ; Storici, Paola ; Ilc, Gregor ; Orlando, Marco ; de Marco, Ario ; Fortuna, Sara

High-resolution structural data of complexes between antibodies and membrane receptors still represent a demanding task. In this study, we used complementary sets of experimental data to obtain a structural model of the complex formed by the human epidermal growth factor receptor 2 (HER2) and its specific nanobody A10. First we identified by NMR the residues that bind or rearrange as a consequence of the complex formation. In parallel, the complex was cross-linked, digested and the resulting peptides were characterized by mass-spectrometry to define maximal distance restraints between HER2 and A10 amino acids in their complex. These independent datasets guided a docking process, refined by molecular dynamics simulations, to develop a model of the complex and estimate per-residue free-energy contributions. Such a model explains the experimental data and identifies a second, non-canonical paratope, located in the region opposite to the conventional nanobody paratope, formed by the hypervariable loop regions LH1 and LH3. Both paratopes contributed substantially to the overall affinity by binding to independent HER2 epitopes. Nanobody mutants with substitution of key interaction residues, as indicated by the model, possess significantly lower affinity for HER2. This is the first described case of a "natural" biparatopic nanobody, directly selected by in-vitro panning.

20 Jan 2021·Bioconjugate ChemistryQ2 · CHEMISTRY

Synthetic Tuning of Domain Stoichiometry in Nanobody–Enzyme Megamolecules

Q2 · CHEMISTRY

Article

Author: Modica, Justin A. ; Kimmel, Blaise R. ; Sykora, Daniel J. ; Werb, Zena ; Dai, Raymond ; Berens, Eric ; Dravid, Vinayak P. ; Parker, Kelly A. ; Metcalf, Kevin J. ; Mrksich, Milan

This paper presents a method to synthetically tune atomically precise megamolecule nanobody-enzyme conjugates for prodrug cancer therapy. Previous efforts to create heterobifunctional protein conjugates suffered from heterogeneity in domain stoichiometry, which in part led to the failure of antibody-enzyme conjugates in clinical trials. We used the megamolecule approach to synthesize anti-HER2 nanobody-cytosine deaminase conjugates with tunable numbers of nanobody and enzyme domains in a single, covalent molecule. Linking two nanobody domains to one enzyme domain improved avidity to a human cancer cell line by 4-fold but did not increase cytotoxicity significantly due to lowered enzyme activity. In contrast, a megamolecule composed of one nanobody and two enzyme domains resulted in an 8-fold improvement in the catalytic efficiency and increased the cytotoxic effect by over 5-fold in spheroid culture, indicating that the multimeric structure allowed for an increase in local drug activation. Our work demonstrates that the megamolecule strategy can be used to study structure-function relationships of protein conjugate therapeutics with synthetic control of protein domain stoichiometry.

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Indication	Highest Phase	Country/Location	Organization	Date
Breast Cancer	Preclinical	US	Allele Biotechnology & Pharmaceuticals, Inc.	-

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