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Formatting and gene-based delivery of a human PD-L1 single domain antibody 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, et al.
(2021) MOLECULAR THERAPY-METHODS & CLINICAL DEVELOPMENT. 22. p.172-182
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Organization
Abstract
Monoclonal antibodies that target the inhibitory immune checkpoint axis consisting of programmed cell death protein 1 (PD-1) and its ligand, PD-L1, have changed the immune-oncology field. Weidentified K2, an anti-humanPD-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 12 GS (glycine-serine) linker, were 313- and 135-fold more potent in enhancing T cell receptor (TCR) signaling in PD-1POS cells than was monovalent K2. We further showed that bivalent constructs generated using a 30GSlinker or disulfide bondwere 169-and 35-fold less potent in enhancing TCR signaling than was 2K2. 2K2 enhanced tumor cell killing in a 3Dmelanoma model, albeit to a lesser extent than avelumab. Therefore, an immunoglobulin (Ig)G1 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 3Dmelanoma model. Overall, this study describes K2-based immune checkpoint medicines, and it highlights the benefit of anIgG1 Fc fusiontoK2 that gains bivalency, effector functions, and efficacy.
Keywords
Genetics, Molecular Biology, Molecular Medicine, LONG-TERM SAFETY, CO-STIMULATION, SOLID TUMORS, PHASE-I, DEATH, SURVIVAL, DESIGN, CELLS, SITE

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MLA
Awad, Robin Maximilian, et al. “Formatting and Gene-Based Delivery of a Human PD-L1 Single Domain Antibody for Immune Checkpoint Blockade.” MOLECULAR THERAPY-METHODS & CLINICAL DEVELOPMENT, vol. 22, 2021, pp. 172–82, doi:10.1016/j.omtm.2021.05.017.
APA
Awad, R. M., Lecocq, Q., Zeven, K., Ertveldt, T., De Beck, L., Ceuppens, H., … Breckpot, K. (2021). Formatting and gene-based delivery of a human PD-L1 single domain antibody for immune checkpoint blockade. MOLECULAR THERAPY-METHODS & CLINICAL DEVELOPMENT, 22, 172–182. https://doi.org/10.1016/j.omtm.2021.05.017
Chicago author-date
Awad, Robin Maximilian, Quentin Lecocq, Katty Zeven, Thomas Ertveldt, Lien De Beck, Hannelore Ceuppens, Katrijn Broos, et al. 2021. “Formatting and Gene-Based Delivery of a Human PD-L1 Single Domain Antibody for Immune Checkpoint Blockade.” MOLECULAR THERAPY-METHODS & CLINICAL DEVELOPMENT 22: 172–82. https://doi.org/10.1016/j.omtm.2021.05.017.
Chicago author-date (all authors)
Awad, Robin Maximilian, 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, and Karine Breckpot. 2021. “Formatting and Gene-Based Delivery of a Human PD-L1 Single Domain Antibody for Immune Checkpoint Blockade.” MOLECULAR THERAPY-METHODS & CLINICAL DEVELOPMENT 22: 172–182. doi:10.1016/j.omtm.2021.05.017.
Vancouver
1.
Awad RM, Lecocq Q, Zeven K, Ertveldt T, De Beck L, Ceuppens H, et al. Formatting and gene-based delivery of a human PD-L1 single domain antibody for immune checkpoint blockade. MOLECULAR THERAPY-METHODS & CLINICAL DEVELOPMENT. 2021;22:172–82.
IEEE
[1]
R. M. Awad et al., “Formatting and gene-based delivery of a human PD-L1 single domain antibody for immune checkpoint blockade,” MOLECULAR THERAPY-METHODS & CLINICAL DEVELOPMENT, vol. 22, pp. 172–182, 2021.
@article{8718416,
  abstract     = {{Monoclonal antibodies that target the inhibitory immune checkpoint axis consisting of programmed cell death protein 1 (PD-1) and its ligand, PD-L1, have changed the immune-oncology field. Weidentified K2, an anti-humanPD-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 12 GS (glycine-serine) linker, were 313- and 135-fold more potent in enhancing T cell receptor (TCR) signaling in PD-1POS cells than was monovalent K2. We further showed that bivalent constructs generated using a 30GSlinker or disulfide bondwere 169-and 35-fold less potent in enhancing TCR signaling than was 2K2. 2K2 enhanced tumor cell killing in a 3Dmelanoma model, albeit to a lesser extent than avelumab. Therefore, an immunoglobulin (Ig)G1 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 3Dmelanoma model. Overall, this study describes K2-based immune checkpoint medicines, and it highlights the benefit of anIgG1 Fc fusiontoK2 that gains bivalency, effector functions, and efficacy.}},
  author       = {{Awad, Robin Maximilian and Lecocq, Quentin and Zeven, Katty and Ertveldt, Thomas and De Beck, Lien and Ceuppens, Hannelore and Broos, Katrijn and De Vlaeminck, Yannick and Goyvaerts, Cleo and Verdonck, Magali and Raes, Geert and Van Parys, Alexander and Cauwels, Anje and Keyaerts, Marleen and Devoogdt, Nick and Breckpot, Karine}},
  issn         = {{2329-0501}},
  journal      = {{MOLECULAR THERAPY-METHODS & CLINICAL DEVELOPMENT}},
  keywords     = {{Genetics,Molecular Biology,Molecular Medicine,LONG-TERM SAFETY,CO-STIMULATION,SOLID TUMORS,PHASE-I,DEATH,SURVIVAL,DESIGN,CELLS,SITE}},
  language     = {{eng}},
  pages        = {{172--182}},
  title        = {{Formatting and gene-based delivery of a human PD-L1 single domain antibody for immune checkpoint blockade}},
  url          = {{http://doi.org/10.1016/j.omtm.2021.05.017}},
  volume       = {{22}},
  year         = {{2021}},
}
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