Controlled release of enhanced cross-hybrid IgGA Fc PD-L1 inhibitors using oncolytic adenoviruses

Firas Hamdan; Michaela Feodoroff; Salvatore Russo; Manlio Fusciello; Sara Feola; Jacopo Chiaro; Gabriella Antignani; Francesca Greco; Jeanette Leusen; Erkko Ylösmäki; Mikaela Grönholm; Vincenzo Cerullo

doi:10.1016/j.omto.2023.01.006

Controlled release of enhanced cross-hybrid IgGA Fc PD-L1 inhibitors using oncolytic adenoviruses

Mol Ther Oncolytics. 2023 Feb 5:28:264-276. doi: 10.1016/j.omto.2023.01.006. eCollection 2023 Mar 16.

Authors

Firas Hamdan^{1

2

3}, Michaela Feodoroff^{1

2

3

4

5}, Salvatore Russo^{1

2

3}, Manlio Fusciello^{1

2

3}, Sara Feola^{1

2

3}, Jacopo Chiaro^{1

2

3}, Gabriella Antignani^{1

2

3}, Francesca Greco¹, Jeanette Leusen⁶, Erkko Ylösmäki^{1

2

3}, Mikaela Grönholm^{1

2

3

5}, Vincenzo Cerullo^{1

2

3

5

7}

Affiliations

¹ Laboratory of Immunovirotherapy, Drug Research Program, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland.
² Translational Immunology Research Program (TRIMM), University of Helsinki, Helsinki, Finland.
³ Drug Delivery, Drug Research Program, Division of Pharmaceutical Biosciences, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland.
⁴ Institute for Molecular Medicine Finland (FIMM), Helsinki Institute of Life Science (HiLIFE), University of Helsinki, Helsinki, Finland.
⁵ iCAN Digital Precision Cancer Medicine Flagship, University of Helsinki, Helsinki, Finland.
⁶ Center for Translational Immunology, University Medical Center Utrecht, Utrecht, the Netherlands.
⁷ Department of Molecular Medicine and Medical Biotechnology and CEINGE, Naples University Federico II, Naples, Italy.

Abstract

Immune checkpoint inhibitors have clinical success in prolonging the life of many cancer patients. However, only a minority of patients benefit from such therapy, calling for further improvements. Currently, most PD-L1 checkpoint inhibitors in the clinic do not elicit Fc effector mechanisms that would substantially increase their efficacy. To gain potency and circumvent off-target effects, we previously designed an oncolytic adenovirus (Ad-Cab) expressing an Fc fusion peptide against PD-L1 on a cross-hybrid immunoglobulin GA (IgGA) Fc. Ad-Cab elicited antibody effector mechanisms of IgG1 and IgA, which led to higher tumor killing compared with each isotype alone and with clinically approved PD-L1 checkpoint inhibitors. In this study, we further improved the therapy to increase the IgG1 Fc effector mechanisms of the IgGA Fc fusion peptide (Ad-Cab FT) by adding four somatic mutations that increase natural killer (NK) cell activation. Ad-Cab FT was shown to work better at lower concentrations compared with Ad-Cab in vitro and in vivo and to have better tumor- and myeloid-derived suppressor cell killing, likely because of higher NK cell activation. Additionally, the biodistribution of the Fc fusion peptide demonstrated targeted release in the tumor microenvironment with minimal or no leakage to the peripheral blood and organs in mice. These data demonstrate effective and safe use of Ad-Cab FT, bidding for further clinical investigation.

Keywords: Fc engineering; IgA; IgG; PD-L1 therapy; oncolytic adenoviruses.