PKPD analysis of soluble CD25 to characterize the concentration-effect relationship observed following the administration of Cergutuzumab Amunaleukin, a targeted immunocytokine for cancer immunotherapy
Hanna E. Silber Baumann (1), Christophe Boetsch (1), Jehad Charo (2), Claire Petry (1), Volker Teichgräber (2), Valerie Cosson (1)
Roche Pharma Research & Early Development. (1) Clinical Pharmacology, Pharmaceutical Sciences, Roche Innovation Center Basel, (2) Roche Innovation Center Zurich.
Objectives: 1. To quantify the concentration-effect relationship of Cergutuzumab Amunaleukin (CA) on the plasma pharmacodynamics (PD) marker soluble CD25 (sCD25), and 2. To support optimization of the dosing regimen of CA by investigating the impact of alternative dosing regimens on sCD25 through simulations.
Methods:
CA is a novel monomeric Carcino Embryonic Antigen (CEA) targeted immunocytokine where a single, engineered IL-2 variant (IL2v) with abolished IL2-Rα (CD25) binding is fused to the C-terminus of a high affinity anti-CEA antibody. Such a molecular design aims to expand CD8 T cells and NK cells while avoiding preferential expansion of regulatory T cells. CD25 is the IL2-Rα unit of the IL-2 receptor and is expressed on activated CD8 T cells as well as on regulatory T cells. sCD25 is shed from proliferating immune cells and has been identified as a marker of peripheral immune activation and possibly efficacy [1].
CA is currently being investigated in early clinical development in solid tumors. In humans, CA displays complex pharmacokinetic (PK) behavior; a model describing the target mediated drug distribution (TMDD) and expansion of the target pool has been presented previously [2,3].
Data from an entry-into human dose escalation study was used for this PKPD analysis. Patients received escalating doses of 0.1-40 mg of CA in weekly (QW) or bi-weekly (Q2W) cycles. sCD25 was sampled up to 4 or 5 cycles for the Q2W and QW regimens, respectively. Patients had on average 8 sCD25 samples, and the PKPD database was composed of 104 patients.
The analysis was performed using NONMEM7.3. A stepwise model development was performed. The parameters of the PK model were kept fixed during the development of the PD model.
Simulations were performed to investigate how the sCD25 profiles can be impacted by different dosing regimens including dose up-titration, induction-maintenance regimens combining QW and Q2W dosing as well as less frequent dosing regimens such as Q3W or Q4W dosing.
Results:
The initial graphical analysis indicated that the expansion of sCD25 was stronger with the QW regimen compared to the Q2W regimen following the initial 4-5 CA administrations, in agreement with the observed immune cell expansion pattern. Following multiple dosing, the magnitude of sCD25 expansion on each cycle was diminished when compared to each pre-dose concentration. This result was in line with the underlying complex PK which results in an expansion of the target pool with an increased clearance and reduced exposure of CA following multiple dosing.
sCD25 was well described using an indirect response (IDR) model with the drug stimulating sCD25 production rate (i.e. shedding). An effect compartment was included to further capture the delay between CA concentrations and the resulting sCD25 profile. The drug effect was best described by a sigmoid Emax model. The parameters of the IDR model were estimated with good precision (RSE<25% for population parameters; RSE<50% for IIV). The proportional residual error was 17% and the IIV ranged between 26 and 60%. The baseline value of sCD25 was incorporated as a covariate on Emax. The model indicated that close to maximum effect would be reached with a well-tolerated dose (15 mg) on cycle 1.
The simulations showed that sCD25 could initially be expanded to higher concentrations with a QW regimen compared to less intense regimens, but that these high concentrations could not be sustained due to the simultaneous induction of clearance by the target cells leading to reduced drug exposure. With a less intense regimen, the sCD25 would reach a new steady state after a few administrations that would be higher than with the QW regimen.
Conclusions: A PKPD model was developed to describe the sCD25 concentration time course upon CA dosing. The model was able to capture the observed exposure-response pattern and was used to support the exploration of additional dosing regimens in the clinic.
References:
[1] Nakata B et al, Serum soluble interleukin-2 receptor level as a prognostic indicator in gastric cancer. British Journal of Cancer (1998) 77(11):1820-1824
[2] HP Grimm et al. PAGE 25 (2016) Abstr 5861 [www.page-meeting.org/?abstract=5861]
[3] Silber Baumann HE et al. When target expression drives drug exposure – an example with the antibody-cytokine fusion protein CEA-IL2v. PSI conference 2016.
