title: Vectorization in an oncolytic vaccinia virus of an antibody, a Fab and a scFv against programmed cell death -1 (PD-1) allows their intratumoral delivery and an improved tumor-growth inhibition.
abstract: We report here the successful vectorization of a hamster monoclonal IgG (namely J43) recognizing the murine Programmed cell death-1 (mPD-1) in Western Reserve (WR) oncolytic vaccinia virus. Three forms of mPD-1 binders have been inserted into the virus: whole antibody (mAb), Fragment antigen-binding (Fab) or single-chain variable fragment (scFv). MAb, Fab and scFv were produced and assembled with the expected patterns in supernatants of cells infected by the recombinant viruses. The three purified mPD-1 binders were able to block the binding of mPD-1 ligand to mPD-1in vitro. Moreover, mAb was detected in tumor and in serum of C57BL/6 mice when the recombinant WR-mAb was injected intratumorally (IT) in B16F10 and MCA 205 tumors. The concentration of circulating mAb detected after IT injection was up to 1,900-fold higher than the level obtained after a subcutaneous (SC) injection (i.e., without tumor) confirming the virus tropism for tumoral cells and/or microenvironment. Moreover, the overall tumoral accumulation of the mAb was higher and lasted longer after IT injection of WR-mAb1, than after IT administration of 10 µg of J43. The IT injection of viruses induced a massive infiltration of immune cells including activated lymphocytes (CD8+and CD4+). Interestingly, in the MCA 205 tumor model, WR-mAb1 and WR-scFv induced a therapeutic control of tumor growth similar to unarmed WR combined to systemically administered J43 and superior to that obtained with an unarmed WR. These results pave the way for next generation of oncolytic vaccinia armed with immunomodulatory therapeutic proteins such as mAbs.
authors.affiliation: Transgene S.A. , Illkirch-Graffenstaden, France.
authors.forename: Patricia
authors.initials: P
authors.lastname: Kleinpeter
authors.affiliation: Transgene S.A., Illkirch-Graffenstaden, France; Institut Gustave Roussy Cancer Campus (GRCC), Villejuif, France.
authors.forename: Laetitia
authors.initials: L
authors.lastname: Fend
authors.affiliation: Transgene S.A. , Illkirch-Graffenstaden, France.
authors.forename: Christine
authors.initials: C
authors.lastname: Thioudellet
authors.affiliation: Transgene S.A. , Illkirch-Graffenstaden, France.
authors.forename: Michel
authors.initials: M
authors.lastname: Geist
authors.affiliation: Transgene S.A. , Illkirch-Graffenstaden, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Sfrontato
authors.affiliation: Transgene S.A. , Illkirch-Graffenstaden, France.
authors.forename: Véronique
authors.initials: V
authors.lastname: Koerper
authors.affiliation: Transgene S.A. , Illkirch-Graffenstaden, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Fahrner
authors.affiliation: Transgene S.A. , Illkirch-Graffenstaden, France.
authors.forename: Doris
authors.initials: D
authors.lastname: Schmitt
authors.affiliation: Transgene S.A. , Illkirch-Graffenstaden, France.
authors.forename: Murielle
authors.initials: M
authors.lastname: Gantzer
authors.affiliation: Transgene S.A. , Illkirch-Graffenstaden, France.
authors.forename: Christelle
authors.initials: C
authors.lastname: Remy-Ziller
authors.affiliation: Transgene S.A. , Illkirch-Graffenstaden, France.
authors.forename: Renée
authors.initials: R
authors.lastname: Brandely
authors.affiliation: Transgene S.A. , Illkirch-Graffenstaden, France.
authors.forename: Dominique
authors.initials: D
authors.lastname: Villeval
authors.affiliation: Transgene S.A. , Illkirch-Graffenstaden, France.
authors.forename: Karola
authors.initials: K
authors.lastname: Rittner
authors.affiliation: Transgene S.A. , Illkirch-Graffenstaden, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Silvestre
authors.affiliation: Transgene S.A. , Illkirch-Graffenstaden, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Erbs
authors.affiliation: Institut Gustave Roussy Cancer Campus (GRCC), Villejuif, France; INSERM U1015, GRCC, Villejuif, France; Center of Clinical Investigations in Biotherapies of Cancer (CICBT) 1418, GRCC, Villejuif, France; University of Paris Sud XI, Kremlin Bicêtre, France; Department of Immuno-Oncology, GRCC, Villejuif, France.
authors.forename: Laurence
authors.initials: L
authors.lastname: Zitvogel
authors.affiliation: Transgene S.A. , Illkirch-Graffenstaden, France.
authors.forename: Eric
authors.initials: E
authors.lastname: Quéméneur
authors.affiliation: Transgene S.A. , Illkirch-Graffenstaden, France.
authors.forename: Xavier
authors.initials: X
authors.lastname: Préville
authors.affiliation: Transgene S.A. , Illkirch-Graffenstaden, France.
authors.forename: Jean-Baptiste
authors.initials: JB
authors.lastname: Marchand
keywords: Monoclonal antibody; PD-1; oncolytic virotherapy; vaccinia virus; vectorization