Development of a quantitative systems pharmacology (QSP) model to support dose optimization of DS-1103a (anti SIRPa antibody) in combination with trastuzumab deruxtecan in patients with cancer.
Authors: Cheng Yougan , Vuppala Pradeep , Sarma Uddipan , Chelliah Viji , Graaf Piet van der , Karibe Tsuyoshi , Hayashi Shinko , Tsubaki Takuya , Kawasaki Norihito , Ishimoto Yoko , Herrmann Monika , Sue Mayumi , Mires Derek E. , Toso John F. , Lau Yvonne Y. , Leil Tarek 
Published: June 2023

e14509 Background: DS-1103a, an anti-human signal regulatory protein α (SIRPα) monoclonal antibody (mAb), is designed to block the SIRPα-CD47 axis “Don’t Eat Me” signal and trigger phagocytosis of tumor cells when combined with an Fc-active antitumor mAb. DS-1103a is being developed as a combination therapy with trastuzumab deruxtecan (T-DXd; DS-8201a) as the antibody-dependent cellular phagocytosis (ADCP) enabling antibody. We developed a QSP model to support the first in human (FIH) intravenous dosing (IV) based on predicted intratumoral receptor occupancy (RO) within immunological synapses (the intercellular contact zone between macrophages and cancer cells) and corresponding ADCP activity. Methods: The QSP model mechanistically integrated DS-1103a plasma pharmacokinetics (PK), tumor distribution and binding of receptors to both antibodies and their ligands to simulate RO in the tumor microenvironment (TME). A proximal pharmacodynamics pathway model was first developed to estimate the intratumoral RO required to induce desired levels of ADCP for DS-1103a+T-DXd combination therapy. A human model was then developed to integrate DS-1103a PK with derived intratumormal RO in patients considering key human pathophysiological parameters, including SIRPα expression, tumor lesion permeability, SIRPα+ cell fractions in TME, tumor capillary radius, SIRPα internalization, CD47 expression and tumor lesion size. Virtual patient simulations were conducted in various cancer types to facilitate FIH dose selection. Results: The proximal pharmacodynamics pathway model quantitatively recapitulated the dose dependent in vitro ADCP activities for DS-1103a+T-DXd combination therapy. The intratumoral RO (within synapses) required to induce desired levels of ADCP activity were also derived. The human model predicted similar dose dependent intratumoral RO in various cancer types. Virtual patient simulations indicated that a flat dose of 100 mg Q3W IV DS-1103a could achieve steady-state intratumoral RO sufficient to reach half of the maximal ADCP activity and would be a suitable FIH starting dose. The predicted steady-state intratumoral RO after a flat dose of ≥1000 mg Q3W IV DS-1103a is well above the predicted intratumoral RO threshold to achieve maximum ADCP activity. Conclusions: The QSP model mechanistically characterized DS-1103a mechanism of action and linked PK to intratumoral RO and corresponding ADCP activity in both in vitro and in vivo setting. The model was used to derive the FIH starting dose and potentially clinically effective doses for DS-1103a in combination with T-DXd. This QSP model will be integrated into a large-scale disease platform to support dose expansion and further dose optimization as new clinical data emerge.