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Comparative evaluation of dimeric and monomeric forms of ADAPT scaffold protein for targeting of HER2-expressing tumours
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
KTH Royal Inst Technol, Dept Prot Technol, SE-10691 Stockholm, Sweden.
KTH Royal Inst Technol, Dept Prot Technol, SE-10691 Stockholm, Sweden.
KTH Royal Inst Technol, Dept Prot Technol, SE-10691 Stockholm, Sweden.ORCID iD: 0000-0002-4695-7858
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2019 (English)In: European journal of pharmaceutics and biopharmaceutics, ISSN 0939-6411, E-ISSN 1873-3441, Vol. 134, p. 37-48Article in journal (Refereed) Published
Abstract [en]

ADAPTs are small engineered non-immunoglobulin scaffold proteins, which have demonstrated very promising features as vectors for radionuclide tumour targeting. Radionuclide imaging of human epidermal growth factor 2 (HER2) expression in vivo might be used for stratification of patients for HER2-targeting therapies. ADAPT6, which specifically binds to HER2, has earlier been shown to have very promising features for in vivo targeting of HER2 expressing tumours. In this study we tested the hypothesis that dimerization of ADAPT6 would increase the apparent affinity to HER2 and accordingly improve tumour targeting. To find an optimal molecular design of dimers, a series of ADAPT dimers with different linkers, -SSSG- (DiADAPT6L1), -(SSSG)(2)- (DiADAPT6L2), and -(SSSG)(3)- (DiADAPT6L3) was evaluated. Dimers in combination with optimal linker lengths demonstrated increased apparent affinity to HER2. The best variants, DiADAPT6L2 and DiADAPT6L3 were site-specifically labelled with In-111 and I-125, and compared with a monomeric ADAPT6 in mice bearing HER2-expressing tumours. Despite higher affinity, both dimers had lower tumour uptake and lower tumour-to-organ ratios compared to the monomer. We conclude that improved affinity of a dimeric form of ADAPT does not compensate the disadvantage of increased size. Therefore, increase of affinity should be obtained by affinity maturation and not by dimerization.

Place, publisher, year, edition, pages
ELSEVIER SCIENCE BV , 2019. Vol. 134, p. 37-48
Keywords [en]
ADAPT, HER2, Dimer, Radionuclide molecular imaging, Indium-111, Iodine-125
National Category
Cancer and Oncology
Identifiers
URN: urn:nbn:se:uu:diva-376893DOI: 10.1016/j.ejpb.2018.11.004ISI: 000456225000004PubMedID: 30408518OAI: oai:DiVA.org:uu-376893DiVA, id: diva2:1288382
Funder
Swedish Research Council, 2015-02353Swedish Research Council, 2015-02509VINNOVA, 2015-02509Swedish Cancer Society, CAN 2015/350Swedish Cancer Society, 2017/425Available from: 2019-02-13 Created: 2019-02-13 Last updated: 2019-02-13Bibliographically approved

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Garousi, Javadvon Witting, EmmaVorobyeva, AnzhelikaOroujeni, MaryamMitran, BogdanOrlova, AnnaBuijs, JosTolmachev, Vladimir
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