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Target Overview
GPC3 is an onco-fetal protein expressed during embryonic development.1 Expression of GPC3 is generally silenced in adult normal tissues,2 but can be reactivated in certain tumors, including liver, lung, clear cell ovarian, esophageal and others.3 GPC3 autologous CAR-T therapies have reported promising preliminary efficacy in HCC,4 providing rationale for developing an off-the-shelf approach.
Compound Overview
AZD9793 is a trispecific T cell engager, which incorporates 2 Fab binding domains to GPC3, one VHH binding domain to TCR and one binding domain to CD8. The VHH domains enable preferential engagement of CD8+ T cells, with the potential to give a broader therapeutic index versus a conventional GPC3xCD3 engager, by reducing CD4+ T cell-associated cytokine release.5,6
Mechanism of Action
References
1. Iglesias BV, Centeno G, Pascuccelli H, et al. Histol Histopathol. 2008;23:1333-1340. 2. Khan S, Blackburn M, Mao DL, et al. Histol Histopathol. 2001;16:71-78. 3. Ishiguro T, Sano Y, Komatsu SI, et al. Sci Transl Med. 2017;9(410):eaal4291. 4. Zhang Q, Fu Q, Cao W, et al. J. Clin. Oncol. 2024;42:4019. 5. Bergamaschi C, Sokhi UK, Youn C et al. J Immunother Cancer. 2024. 6. Bergamaschi C, Lovatt C, Sokhi UK et al. Cancer Res. 2025.
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Abbreviations
CAR-T
chimeric antigen receptor T cell (therapy)
CD3
cluster of differentiation 3
CD4
cluster of differentiation 4
CD8
cluster of differentiation 8
Fab
fragment antigen binding
GPC3
glypican 3
HCC
hepatocellular carcinoma
IFNγ
interferon γ
TCR
T-cell receptor
VHH
variable domain of the heavy-chain
Target Overview
GPC3 is an onco-fetal protein expressed during embryonic development.1 Expression of GPC3 is generally silenced in adult normal tissues,2 but can be reactivated in certain tumors, including liver, lung, clear cell ovarian, esophageal and others.3 GPC3 autologous CAR-T therapies have reported promising preliminary efficacy in HCC,4 providing rationale for developing an off-the-shelf approach.
Compound Overview
AZD9793 is a trispecific T cell engager, which incorporates 2 Fab binding domains to GPC3, one VHH binding domain to TCR and one binding domain to CD8. The VHH domains enable preferential engagement of CD8+ T cells, with the potential to give a broader therapeutic index versus a conventional GPC3xCD3 engager, by reducing CD4+ T cell-associated cytokine release.5,6
Mechanism of Action
References
1. Iglesias BV, Centeno G, Pascuccelli H, et al. Histol Histopathol. 2008;23:1333-1340. 2. Khan S, Blackburn M, Mao DL, et al. Histol Histopathol. 2001;16:71-78. 3. Ishiguro T, Sano Y, Komatsu SI, et al. Sci Transl Med. 2017;9(410):eaal4291. 4. Zhang Q, Fu Q, Cao W, et al. J. Clin. Oncol. 2024;42:4019. 5. Bergamaschi C, Sokhi UK, Youn C et al. J Immunother Cancer. 2024. 6. Bergamaschi C, Lovatt C, Sokhi UK et al. Cancer Res. 2025.
Clinical trial information
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Abbreviations
CAR-T
chimeric antigen receptor T cell (therapy)
CD3
cluster of differentiation 3
CD4
cluster of differentiation 4
CD8
cluster of differentiation 8
Fab
fragment antigen binding
GPC3
glypican 3
HCC
hepatocellular carcinoma
IFNγ
interferon γ
TCR
T-cell receptor
VHH
variable domain of the heavy-chain