title: Efficacy of an adapted granzyme B-based anti-CD30 cytolytic fusion protein against PI-9-positive classical Hodgkin lymphoma cells in a murine model.
abstract: Tumors develop when infiltrating immune cells contribute growth stimuli, and cancer cells are selected to survive within such a cytotoxic microenvironment. One possible immune-escape mechanism is the upregulation of PI-9 (Serpin B9) within cancer cells. This serine proteinase inhibitor selectively inactivates apoptosis-inducing granzyme B (GrB) from cytotoxic granules of innate immune cells. We demonstrate that most classical Hodgkin lymphoma (cHL)-derived cell lines express PI-9, which protects them against the GrB attack and thereby renders them resistant against GrB-based immunotherapeutics. To circumvent this disadvantage, we developed PI-9-insensitive human GrB mutants as fusion proteins to target the Hodgkin-selective receptor CD30. In contrast to the wild-type GrB, a R201K point-mutated GrB construct most efficiently killed PI-9-positive and -negative cHL cells. This was tested in vitro and also in vivo whereby a novel optical imaging-based tumor model with HL cell line L428 was applied. Therefore, this variant, as part of the next generation immunotherapeutics, also named cytolytic fusion proteins showing reduced immunogenicity, is a promising molecule for (targeted) therapy of patients with relapsing malignancies, such as cHL, and possibly other PI-9-positive malignancies, such as breast or lung carcinoma.
authors.affiliation: 1] Department of Experimental Medicine and Immunotherapy, RWTH Aachen, Helmholtz Institute for Biomedical Engineering, Aachen, Germany [2] Department of Pharmaceutical Product Development, Fraunhofer Institute for Molecular Biology and Applied Ecology IME, Aachen, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Schiffer
authors.forename: H P
authors.initials: HP
authors.lastname: Hansen
authors.forename: G
authors.initials: G
authors.lastname: Hehmann-Titt
authors.forename: M
authors.initials: M
authors.lastname: Huhn
authors.forename: R
authors.initials: R
authors.lastname: Fischer
authors.forename: S
authors.initials: S
authors.lastname: Barth
authors.forename: T
authors.initials: T
authors.lastname: Thepen