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EP40034
Abstract: Objectives: Bispecific monoclonal antibodies (BsAbs) target two different surface molecules on cancer and/or immune cells by binding two different targets. The objective of this study is to predict pharmacokinetics (PK), receptor occupancy (RO), and optimal dose for a bispecific antibody YH008 [1] against CD40 and PD1 using a PBPK/RO model.
Methods: The PBPK/RO model describes distribution of a BsAb between physiological compartments (plasma, tumor, tumor-draining lymph nodes, other tissues and lymph nodes), transport across the endothelium, binding with CD40 on dendritic cells (DCs), B cells, and macrophages (Mph) and PD1 on CD4+ and CD8+ T cells in immunological synapses (ISs). The model takes into account cell numbers in different compartments and expression of the target molecules and their ligands, clearance of the BsAb, effect of the BsAb on production of interferon γ (IFNγ), and IFNγ effect on CD40 expression. Kinetic parameters of YH008 binding with CD40 and PD1 were taken from [1]. The model was validated using PK data on mAbs against CD40 and PD1. The optimal dose and dosing regimen for YH008 were selected based on the exposure/area under curve (AUC) of the PD1-PDL1, CD40L-3CD40, CD40-YH008-PD1 complexes.
Results: Validation of the model shows good agreement with the experimental PK and RO data for monospecific mAbs against PD1 (Pembrolizumab) and CD40 (Selicrelumab, BI 655064, Chi Lob 7/4). In tumor, 95% RO on antigen-presenting cells and 85% RO on T cells are achieved at single dose of 240 mg.
The studied BsAb exerts its effect by disrupting immunosuppressive PD1-PDL1 complexes through binding with PD1 on T cells and by engaging CD40 on APCs. In the model, higher levels of PD1-YH008-CD40 and CD40L-3CD40 complexes translate into higher activation of APCs, and lower levels of PD1-PDL1 complexes translate into lower inhibition of T cells. Functions describing these effects through AUCs for the complexes show that the balance between these processes is achieved at intermediate doses of the BsAb (20-120 mg/week). Changes in dosing regimen do not substantially affect PD1-PDL1 complex disruption but can affect stimulatory signaling through CD40 and PD1-YH008-CD40 trimer.
Conclusions: The developed PBPK/RO model for a BsAb based on physiological levels of immune cells, target molecule numbers, and binding parameters for YH008 antibody against CD40 and PD1 predicts PK and RO in blood and tumor. The proposed approach to optimal dose prediction shows that the balance between different physiologically active complexes is achieved at doses between 20 and 120 mg/week.Summary: The developed PBPK/RO model for a BsAb based on physiological levels of immune cells, target molecule numbers, and binding parameters for YH008 antibody against CD40 and PD1 predicts PK and RO in blood and tumor. The proposed approach to optimal dose prediction shows that the balance between different physiologically active complexes is achieved at doses between 20 and 120 mg/week.References: [1] Baihong Liu, et al. (2021) A Novel PD1-CD40 Bispecific Antibody YH008 Induces Potent Anti-tumor Activity in-vivo by PD1 Dependent Activation of CD40 Signaling, AACR2021 poster
ACoP13 (2022) QSP-375 [www.go-acop.org/?abstract=375]
{https://insysbio.com/our-expertise/posters/}
Methods: The PBPK/RO model describes distribution of a BsAb between physiological compartments (plasma, tumor, tumor-draining lymph nodes, other tissues and lymph nodes), transport across the endothelium, binding with CD40 on dendritic cells (DCs), B cells, and macrophages (Mph) and PD1 on CD4+ and CD8+ T cells in immunological synapses (ISs). The model takes into account cell numbers in different compartments and expression of the target molecules and their ligands, clearance of the BsAb, effect of the BsAb on production of interferon γ (IFNγ), and IFNγ effect on CD40 expression. Kinetic parameters of YH008 binding with CD40 and PD1 were taken from [1]. The model was validated using PK data on mAbs against CD40 and PD1. The optimal dose and dosing regimen for YH008 were selected based on the exposure/area under curve (AUC) of the PD1-PDL1, CD40L-3CD40, CD40-YH008-PD1 complexes.
Results: Validation of the model shows good agreement with the experimental PK and RO data for monospecific mAbs against PD1 (Pembrolizumab) and CD40 (Selicrelumab, BI 655064, Chi Lob 7/4). In tumor, 95% RO on antigen-presenting cells and 85% RO on T cells are achieved at single dose of 240 mg.
The studied BsAb exerts its effect by disrupting immunosuppressive PD1-PDL1 complexes through binding with PD1 on T cells and by engaging CD40 on APCs. In the model, higher levels of PD1-YH008-CD40 and CD40L-3CD40 complexes translate into higher activation of APCs, and lower levels of PD1-PDL1 complexes translate into lower inhibition of T cells. Functions describing these effects through AUCs for the complexes show that the balance between these processes is achieved at intermediate doses of the BsAb (20-120 mg/week). Changes in dosing regimen do not substantially affect PD1-PDL1 complex disruption but can affect stimulatory signaling through CD40 and PD1-YH008-CD40 trimer.
Conclusions: The developed PBPK/RO model for a BsAb based on physiological levels of immune cells, target molecule numbers, and binding parameters for YH008 antibody against CD40 and PD1 predicts PK and RO in blood and tumor. The proposed approach to optimal dose prediction shows that the balance between different physiologically active complexes is achieved at doses between 20 and 120 mg/week.Summary: The developed PBPK/RO model for a BsAb based on physiological levels of immune cells, target molecule numbers, and binding parameters for YH008 antibody against CD40 and PD1 predicts PK and RO in blood and tumor. The proposed approach to optimal dose prediction shows that the balance between different physiologically active complexes is achieved at doses between 20 and 120 mg/week.References: [1] Baihong Liu, et al. (2021) A Novel PD1-CD40 Bispecific Antibody YH008 Induces Potent Anti-tumor Activity in-vivo by PD1 Dependent Activation of CD40 Signaling, AACR2021 poster
ACoP13 (2022) QSP-375 [www.go-acop.org/?abstract=375]
{https://insysbio.com/our-expertise/posters/}
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