Gene-based delivery of human PD-L1 single domain antibody formats for immune checkpoint blockade

Robin Maximilian Awad, Quentin Lecocq, Katty Zeven, Thomas Ertveldt, Lien De Beck, Hannelore Ceuppens, Katrijn Broos, Yannick De Vlaeminck, Cleo Goyvaerts, Magali Verdonck, Geert Raes, Alexander Van Parys, Anje Cauwels, Marleen Keyaerts, Nick Devoogdt, Karine Breckpot

Onderzoeksoutput: Unpublished abstract

108 Downloads (Pure)

Samenvatting

General audience description: Cancer cells use a protein called PD-L1 to paralyze immune cells with cancer killing abilities. We enhanced the potency of K2, a fragment of camel antibodies that binds PD-L1 and as such inhibits PD-L1’s immune paralyzing effects.

Abstract: Monoclonal antibodies that target the inhibitory immune checkpoint axis consisting of PD-1 and its ligand, PD-L1, have changed the immune-oncology field. We identified K2, an anti-human PD-L1 single domain antibody fragment, that can enhance T-cell activation and tumor cell killing. In this study, the potential of different K2 formats as immune checkpoint blocking medicines was evaluated using a gene-based delivery approach. We showed that 2K2 and 3K2, a bivalent and trivalent K2 format generated using a 12GS linker, were 313- and 135-fold more potent in enhancing T-cell receptor (TCR) signaling in PD-1 positive cells than monovalent K2. We further showed that bivalent constructs generated using a 30GS linker or disulfide bond were 169- and 35-fold less potent in enhancing TCR signaling than 2K2. 2K2 enhanced tumor cell killing in a 3D melanoma model, albeit to a lesser extent than avelumab. Therefore, an IgG1 antibody-like fusion protein was generated, referred to as K2-Fc. K2-Fc was significantly better than avelumab in enhancing tumor cell killing in the 3D melanoma model. Overall, this study describes a new immune checkpoint medicine, and highlights the benefit of an IgG1 Fc-fusion to K2 that gains bivalency, effector functions and efficacy.
Originele taal-2English
StatusPublished - 22 feb. 2021
EvenementAnnual retreat of the Melanoma Research Alliance - Digital Event, Washington, United States
Duur: 22 feb. 202123 feb. 2021

Conference

ConferenceAnnual retreat of the Melanoma Research Alliance
Land/RegioUnited States
StadWashington
Periode22/02/2123/02/21

Vingerafdruk

Duik in de onderzoeksthema's van 'Gene-based delivery of human PD-L1 single domain antibody formats for immune checkpoint blockade'. Samen vormen ze een unieke vingerafdruk.

Citeer dit