title: Characterization of the first-in-class T-cell-engaging bispecific single-chain antibody for targeted immunotherapy of solid tumors expressing the oncofetal protein claudin 6.
abstract: The fetal tight junction molecule claudin 6 (CLDN6) is virtually absent from any normal tissue, whereas it is aberrantly and frequently expressed in various cancers of high medical need. We engineered 6PHU3, a T-cell-engaging bispecific single chain molecule (bi-(scFv)2) with anti-CD3/anti-CLDN6 specificities, and characterized its pharmacodynamic properties. Our data show that upon engagement by 6PHU3, T cells strongly upregulate cytotoxicity and activation markers, proliferate and acquire an effector phenotype. 6PHU3 exerts potent killing of cancer cellsin vitrowith EC50values in the pg/mL range. Subcutaneous xenograft tumors in NSG mice engrafted with human PBMCs are eradicated by 6PHU3 treatment and survival of mice is significantly prolonged. Tumors of 6PHU3-treated mice are strongly infiltrated with activated CD4+, CD8+T cells and TEMtype cells but not Tregsand display a general activation of a mostly inflammatory phenotype. These effects are only observed upon bispecific but not monospecific engagement of 6PHU3. Together with the exceptionally cancer cell selective expression of the oncofetal tumor marker CLDN6, this provides a safeguard with regard to toxicity. In summary, our data shows that the concept of T-cell redirection combined with that of highly selective targeting of CLDN6-positive solid tumors is effective. Thus, exploring 6PHU3 for clinical therapy is warranted.
authors.affiliation: Biopharmaceutical New Technologies (BioNTech) AG, Mainz, Germany; TRON - Translational Oncology at the University Medical Center of the Johannes Gutenberg University gGmbH, Mainz, Germany.
authors.forename: Christiane R
authors.initials: CR
authors.lastname: Stadler
authors.affiliation: Biopharmaceutical New Technologies (BioNTech) AG, Mainz, Germany; TRON - Translational Oncology at the University Medical Center of the Johannes Gutenberg University gGmbH, Mainz, Germany.
authors.forename: Hayat
authors.initials: H
authors.lastname: Bähr-Mahmud
authors.affiliation: Biopharmaceutical New Technologies (BioNTech) AG, Mainz, Germany; TRON - Translational Oncology at the University Medical Center of the Johannes Gutenberg University gGmbH, Mainz, Germany.
authors.forename: Laura M
authors.initials: LM
authors.lastname: Plum
authors.affiliation: Biopharmaceutical New Technologies (BioNTech) AG, Mainz, Germany; TRON - Translational Oncology at the University Medical Center of the Johannes Gutenberg University gGmbH, Mainz, Germany.
authors.forename: Kathrin
authors.initials: K
authors.lastname: Schmoldt
authors.affiliation: TRON - Translational Oncology at the University Medical Center of the Johannes Gutenberg University gGmbH , Mainz, Germany.
authors.forename: Anne C
authors.initials: AC
authors.lastname: Kölsch
authors.affiliation: Ganymed Pharmaceuticals AG , Mainz, Germany.
authors.forename: Özlem
authors.initials: Ö
authors.lastname: Türeci
authors.affiliation: Biopharmaceutical New Technologies (BioNTech) AG, Mainz, Germany; TRON - Translational Oncology at the University Medical Center of the Johannes Gutenberg University gGmbH, Mainz, Germany; Department for Internal Medicine, Johannes Gutenberg University, III; Mainz, Germany.
authors.forename: Ugur
authors.initials: U
authors.lastname: Sahin
keywords: Bispecific antibody; T cell engagement; T-cell engager; ideal target; oncofetal tumor marker; solid tumors; targeted immunotherapy; tumor-infiltrating lymphocytes; xenograft mouse model