Abstract 1019P
Background
ALX148 is a promising CD47 blocking agent currently undergoing clinical trials. Optimal dose selection can be guided by the assessment of target receptor occupancy (RO) and pharmacodynamics (PD) effect in the site of action. While direct measurement of actual RO in the tumor tissues is challenging, mechanistic pharmacokinetic (PK) RO and PD modelling can provide valuable information that can be extrapolated to the clinic. The aims of this study were: (1) to develop mechanistic PK/RO model for ALX148 capable to predict target RO in the tumor tissues and periphery of cancer patients; (2) to estimate PD effect of ALX148 on of phagocytosis; (3) to determine optimal dosage regimes for ALX148.
Methods
A semi-mechanistic PK/RO/PD model was developed. PK of ALX148 and its distribution to the tumor tissues (lymph nodes, spleen and bone marrow) were described in the model. The model includes non-linear clearance of ALX148 due to target CD47 receptor binding and further internalization of the complex. CD47 RO was described on red blood cells and tumor cells taking into account the amount of cells and CD47 expression (molecules per cell). Parameters were fitted against clinical PK and in vitro data. Clinical data on CD47 RO in the periphery was used for model validation.
Results
The model successfully described ALX148 clinical PK and RO data. Predicted trough CD47 RO in spleen, lymph nodes and bone marrow were similar and median value was about 98% (range: 94%-100%) during the treatment with 10 mg/kg QW of ALX148. Further dose escalation didn’t significantly increase CD47 RO. Phagocytosis of cancer cells was predicted to be increased by ∼1.8 times (range: 1-3 times) during the treatment with both regimens of ALX148: 10 mg/kg and 30 mg/kg QW. Dose 3 mg/kg resulted in the lower induction of phagocytosis than 10 mg/kg: 1.6 vs 1.8 (p-value <0.001).
Conclusions
Developed model predicted that 10 mg/kg QW is an optimal dose of ALX148 to occupy more than 90% of CD47 in the tumor tissues to achieve maximal induction of phagocytosis. This approach can be applied for the optimal dose selection of other anti-CD47 agents taking into account their specific features as binding properties, size, etc.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
InSysBio.
Funding
Has not received any funding.
Disclosure
All authors have declared no conflicts of interest.