M. Stroh (1), K. Williams (2), T. Ho (1), J.F. Apgar (2), and W. Michael Kavanaugh (1)
(1) CytomX Therapeutics, South San Francisco, CA, USA, (2) Applied BioMath, Concord, MA, USA.
Introduction: CD71 is an attractive, yet undruggable, antibody drug conjugate (ADC) target due to broad and high expression in normal tissues, resulting in on-target toxicity outside the tumor microenvironment. Probody® therapeutics (Pb-Tx) are antibody prodrugs with cleavable peptide masks designed to reduce off-tumor, on-target toxicities [1]. The peptide mask inhibits Pb-Tx binding in the periphery yet can be removed by tumor-associated proteases resulting in intratumoral activation. CX-2029/ ABBV-2029 s a CD71-targeting Probody drug conjugate (PDC) composed of a Pb-Tx conjugated to the cytotoxin MMAE via a cysteine protease cleavable dipeptide val-cit linker; CX-2029/ ABBV-2029 is currently under investigation for the treatment of cancer (NCT03543813).
Objective: The study aim is to develop a quantitative systems pharmacology (QSP) model for the clinical translation of CX-2029/ ABBV-2029.
Methods: CX-2030 is an unmasked ADC which shares target, MMAE warhead, and drug:antibody ratios (~2) with CX-2029/ ABBV-2029. Pharmacokinetic (PK) and absolute neutrophil count (ANC) samples were collected at prespecified times following administration of PDC CX-2029/ ABBV-2029 2, 6, and 12 mg/kg and ADC CX-2030 0.6, 2, and 6 mg/kg to cynomolgus monkeys.
A QSP Pb-Tx model was developed and calibrated against PK and ANC data in the cynomolgus monkey. Models were implemented using KroneckerBio v. 0.4 (https://github.com/kroneckerbio) and expressed as a system of ordinary differential equations with the following form:
dx/dt=k+Ax+B (x⊗x)
where k is a vector of 0th order rate constants, A is an n by n matrix of 1st order rate constants, and B is an n by n matrix of second order rate constants. Parameter estimation and simulations were performed using MATLAB v. 2017a (Mathworks, Natick MA).
Results: The QSP Pb-Tx model was developed based on proposed mechanisms of Pb-Tx distribution, elimination, activation and binding [2]. The QSP Pb-Tx model has provisions both at the Pb-Tx- and compartmental- levels. Model provisions for the Pb-Tx include reversible mask equilibrium binding (“breathing”) events and irreversible cleavage reactions; this yields multiple species that may interact with CD71 with differential affinities. Common to other monoclonal antibody pharmacology models [3], the multiple states of the Pb-Tx distribute to the plasma, peripheral, and tumor compartments. The PDC CX-2029/ ABBV-2029 and ADC CX-2030 effects on ANC were in turn captured using QSP model-predicted peripheral receptor occupancy (RO) and a modified myelosuppression model of Friberg et al [4].
In monkeys, QSP predictions suggested increased target-mediated drug disposition (TMDD) for ADC CX-2030 relative to PDC CX-2029/ ABBV-2029. The QSP Pb-Tx model predictions indicated that there would be decreased peripheral RO for PDC CX-2029/ ABBV-2029 relative to ADC CX-2030. Predictions captured the steeper dose-effect of ANC at nadir for ADC CX-2030 relative to PDC CX-2029/ ABBV-2029. Human projections suggested both decreased TMDD and increased tolerability for PDC CX-2029/ ABBV-2029 relative to ADC CX-2030.
Conclusion: The QSP model captures the determinants of PDC CX-2029/ ABBV-2029 PK/PD in monkeys and mechanistically projects safer targeting of CD71 in the clinic by PDC CX-2029/ ABBV-2029.
References:
[1] Desnoyers LR, Vasiljeva O, Richardson JH, Yang A, Menendez EE, Liang TW, et al. Tumor-specific activation of an EGFR-targeting probody enhances therapeutic index. Sci Transl Med. 2013;5(207):207ra144.
[2] Stroh M, Sagert J, Burke JM, Apgar JF, Lin L, Millard BL, et al. Quantitative Systems Pharmacology Model of a Masked, Tumor-Activated Antibody. CPT: pharmacometrics & systems pharmacology. 2019;8(9):676-84.
[3] Baxter LT, Zhu H, Mackensen DG, Jain RK. Physiologically based pharmacokinetic model for specific and nonspecific monoclonal antibodies and fragments in normal tissues and human tumor xenografts in nude mice. Cancer Res. 1994;54(6):1517-28.
[4] Friberg LE, Henningsson A, Maas H, Nguyen L, Karlsson MO. Model of chemotherapy-induced myelosuppression with parameter consistency across drugs. J Clin Oncol. 2002;20(24):4713-21.
Reference: PAGE () Abstr 9411 [www.page-meeting.org/?abstract=9411]
Poster: Drug/Disease Modelling - Oncology