Data from Relative Target Affinities of T-Cell–Dependent Bispecific Antibodies Determine Biodistribution in a Solid Tumor Mouse Model

• DOI: 10.1158/1535-7163.c.6539608.v1
• Publication Date: 2023-04-04T03:17:29Z
• Authors: Danielle Mandikian; Nene Takahashi; Amy A. Lo; Ji Li; Jeffrey Eastham-A...; Dionysos Slaga; Jason Ho; Maria Hristopoulos; Robyn Clark; Klara Totpal; Kedan Lin; Sean B. Joseph; Mark S. Dennis; Saileta Prabhu; Teemu T. Junttila; C. Andrew Boswell
• Keywords: Biodistribution

<div>Abstract<p>Anti-HER2/CD3, a T-cell–dependent bispecific antibody (TDB) construct, induces T-cell–mediated cell death in cancer cells expressing HER2 by cross-linking tumor with CD3 on cytotoxic T cells, thereby creating functional cytolytic synapse. TDB design is very challenging process that requires consideration of multiple parameters. Although therapeutic strategy commonly driven striving for the highest attainable antigen-binding affinity, little known about how affinity each arm can affect targeting ability other and consequent distribution efficacy. To our knowledge, no studies have been published using preclinical models wherein T-cell–targeting actively bound to cells. We used combined approach involving radiochemistry, invasive biodistribution, noninvasive single-photon emission tomographic (SPECT) imaging measure catabolism transgenic mice human CD3ϵ expression Using variants, we assessed impact short-term pharmacokinetics, tissue distribution, cellular uptake. Our experimental determined relative effects (i) normal tissues, (ii) HER2-expressing tumors, (iii) HER2/CD3 all as critical drivers distribution. observed strong correlation between T-cell–rich higher reducing systemic exposure shifting away from T-cell–containing tissues. These observations important implications clinical translation antibodies immunotherapy. <i>Mol Cancer Ther; 17(4); 776–85. ©2018 AACR</i>.</p></div>