New TEM1 targeting antibodies for radioimmunotherapy: In vitro, in vivo and in silico studies

Authors and Affiliations: 

D'Onofrio A.¹, Gano L.^1,2, Melo R.¹, Mendes F.^1,2, Oliveira M. C.^1,2, Denoël T.³, Schaefer N.³, Viertl D.³, Fierle J.⁴, Coukos G.⁵, Dunn S.⁴, Prior J. O.³, Paulo A.^1,2

¹ C²TN- Centro de Ciências e Tecnologias Nucleares, Instituto Superior Técnico, Universidade de Lisboa, Portugal

² DECN - Departamento de Engenharia e Ciências Nucleares, Instituto Superior Técnico, Universidade de Lisboa, Portugal

³ Department of Nuclear Medicine and Molecular Imaging, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland

⁴ LAbCore, Ludwig Institute for Cancer Research, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland

⁵ Ludwig Institute for Cancer Research and Department of Oncology, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland

Abstract:

The tumour endothelial marker 1 (TEM1/endosialin/CD248) is a receptor overexpressed in several human solid tumours and silenced in normal adult tissues, representing a suitable and potentially safe target for radioimmunotherapy of sarcoma. To develop new tools with improved TEM1 targeting properties, a new panel of antibody fragments was for the first time evaluated preclinically following ¹²⁵I radiolabelling. The antibody fragment 1C1m-Fc, with the highest human/murine TEM1 binding affinity, was extensively characterized in vitro and in vivo in a Ewing’s sarcoma human xenograft mouse model. In silico studies were also performed to elucidate the influence of a single amino acid mutation in the complementarity-determining region (CDR3) of the heavy chain, upon affinity maturation of the parental clone 1C1-Fc. From this study, 1C1m-Fc emerged as a promising candidate for the development of TEM1-targeted radioimmunoconjugates, namely to be further explored for theranostic applications with other suitable medical radionuclides.

Journal: European Journal of Pharmaceutics and Biopharmaceutics

Link: https://doi.org/10.1016/j.ejpb.2020.11.015