PMID- 30321203 OWN - NLM STAT- MEDLINE DCOM- 20190326 LR - 20190326 IS - 1932-6203 (Electronic) IS - 1932-6203 (Linking) VI - 13 IP - 10 DP - 2018 TI - An approved in vitro approach to preclinical safety and efficacy evaluation of engineered T cell receptor anti-CD3 bispecific (ImmTAC) molecules. PG - e0205491 LID - 10.1371/journal.pone.0205491 [doi] LID - e0205491 AB - Robust preclinical testing is essential to predict clinical safety and efficacy and provide data to determine safe dose for first-in-man studies. There are a growing number of examples where the preclinical development of drugs failed to adequately predict clinical adverse events in part due to their assessment with inappropriate preclinical models. Preclinical investigations of T cell receptor (TCR)-based immunotherapies prove particularly challenging as these biologics are human-specific and thus the conventional testing in animal models is inadequate. As these molecules harness the full force of the immune system, and demonstrate tremendous potency, we set out to design a preclinical package that would ensure adequate evaluation of these therapeutics. Immune Mobilising Monoclonal TCR Against Cancer (ImmTAC) molecules are bi-specific biologics formed of an affinity-enhanced TCR fused to an anti-CD3 effector function. ImmTAC molecules are designed to activate human T lymphocytes and target peptides within the context of a human leukocyte antigen (HLA), thus require an intact human immune system and peptidome for suitable preclinical screening. Here we draw upon the preclinical testing of four ImmTAC molecules, including IMCgp100, the first ImmTAC molecule to reach the clinic, to present our comprehensive, informative and robust approach to in vitro preclinical efficacy and safety screening. This package comprises a broad range of cellular and molecular assays using human tissues and cultured cells to test efficacy, safety and specificity, and hence predict human responses in clinical trials. We propose that this entirely in vitro package offers a potential model to be applied to screening other TCR-based biologics. FAU - Harper, Jane AU - Harper J AD - Immunocore Ltd, Abingdon, Oxford, United Kingdom. FAU - Adams, Katherine J AU - Adams KJ AD - Adaptimmune, Oxford, United Kingdom. FAU - Bossi, Giovanna AU - Bossi G AD - Immunocore Ltd, Abingdon, Oxford, United Kingdom. FAU - Wright, Debbie E AU - Wright DE AD - Immunocore Ltd, Abingdon, Oxford, United Kingdom. FAU - Stacey, Andrea R AU - Stacey AR AD - Immunocore Ltd, Abingdon, Oxford, United Kingdom. FAU - Bedke, Nicole AU - Bedke N AD - Immunocore Ltd, Abingdon, Oxford, United Kingdom. FAU - Martinez-Hague, Ruth AU - Martinez-Hague R AD - Immunocore Ltd, Abingdon, Oxford, United Kingdom. FAU - Blat, Dan AU - Blat D AD - Immunocore Ltd, Abingdon, Oxford, United Kingdom. FAU - Humbert, Laure AU - Humbert L AD - Immunocore Ltd, Abingdon, Oxford, United Kingdom. FAU - Buchanan, Hazel AU - Buchanan H AD - Immunocore Ltd, Abingdon, Oxford, United Kingdom. FAU - Le Provost, Gabrielle S AU - Le Provost GS AD - Immunocore Ltd, Abingdon, Oxford, United Kingdom. FAU - Donnellan, Zoe AU - Donnellan Z AD - Immunocore Ltd, Abingdon, Oxford, United Kingdom. FAU - Carreira, Ricardo J AU - Carreira RJ AUID- ORCID: 0000-0002-7705-1354 AD - Immunocore Ltd, Abingdon, Oxford, United Kingdom. FAU - Paston, Samantha J AU - Paston SJ AD - Immunocore Ltd, Abingdon, Oxford, United Kingdom. FAU - Weigand, Luise U AU - Weigand LU AD - Immunocore Ltd, Abingdon, Oxford, United Kingdom. FAU - Canestraro, Martina AU - Canestraro M AD - Immunocore Ltd, Abingdon, Oxford, United Kingdom. FAU - Sanderson, Joseph P AU - Sanderson JP AD - Adaptimmune, Oxford, United Kingdom. FAU - Botta Gordon-Smith, Sophie AU - Botta Gordon-Smith S AUID- ORCID: 0000-0002-6255-6130 AD - Immunocore Ltd, Abingdon, Oxford, United Kingdom. FAU - Lowe, Kate L AU - Lowe KL AD - Immunocore Ltd, Abingdon, Oxford, United Kingdom. FAU - Rygiel, Karolina A AU - Rygiel KA AD - Immunocore Ltd, Abingdon, Oxford, United Kingdom. FAU - Powlesland, Alex S AU - Powlesland AS AD - Immunocore Ltd, Abingdon, Oxford, United Kingdom. FAU - Vuidepot, Annelise AU - Vuidepot A AD - Immunocore Ltd, Abingdon, Oxford, United Kingdom. FAU - Hassan, Namir J AU - Hassan NJ AD - Immunocore Ltd, Abingdon, Oxford, United Kingdom. FAU - Cameron, Brian J AU - Cameron BJ AD - Immunocore Ltd, Abingdon, Oxford, United Kingdom. FAU - Jakobsen, Bent K AU - Jakobsen BK AD - Immunocore Ltd, Abingdon, Oxford, United Kingdom. FAU - Dukes, Joseph AU - Dukes J AD - Immunocore Ltd, Abingdon, Oxford, United Kingdom. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20181015 PL - United States TA - PLoS One JT - PloS one JID - 101285081 RN - 0 (Antibodies, Bispecific) RN - 0 (ImmTAC molecule, human) RN - 0 (Proteins) RN - 0 (Single-Chain Antibodies) SB - IM MH - Antibodies, Bispecific/*pharmacology MH - Cell Line, Tumor MH - Cell Proliferation/drug effects MH - Cell Survival/drug effects MH - Drug Screening Assays, Antitumor/*methods MH - Humans MH - In Vitro Techniques MH - Proteins/*pharmacology MH - Single-Chain Antibodies/*pharmacology MH - Workflow PMC - PMC6188753 COIS- All authors are/were employees of Immunocore Ltd and the study was entirely funded by this organisation. IMCgp100 biologic is an investigational new drug produced by Immunocore Ltd. This does not alter our adherence to PLOS ONE policies on sharing data and materials. EDAT- 2018/10/16 06:00 MHDA- 2019/03/27 06:00 PMCR- 2018/10/15 CRDT- 2018/10/16 06:00 PHST- 2018/05/17 00:00 [received] PHST- 2018/07/27 00:00 [accepted] PHST- 2018/10/16 06:00 [entrez] PHST- 2018/10/16 06:00 [pubmed] PHST- 2019/03/27 06:00 [medline] PHST- 2018/10/15 00:00 [pmc-release] AID - PONE-D-18-14850 [pii] AID - 10.1371/journal.pone.0205491 [doi] PST - epublish SO - PLoS One. 2018 Oct 15;13(10):e0205491. doi: 10.1371/journal.pone.0205491. eCollection 2018.