087: Development of a Pharmacokinetic-Tumor Target Engagement Model Using Nonclinical Data to Inform Phase 1 Dosing Scheme for a Novel Bispecific CD40-EpCAM Antibody, KK2269

Statement of Purpose, Innovation or Hypothesis: Several systemic CD40 agonists have been investigated as potential cancer immunotherapies. However, systemic toxicities may limit these antibodies from exerting their full activity¹. KK2269 is a recombinant fully human immunoglobulin G subclass 4 (IgG4) bispecific antibody targeting EpCAM and CD40 receptors. Nonclinical studies demonstrated that KK2269 exerts CD40 agonistic signals on dendritic cells (DCs) only when the antibody is cross-linked to EpCAM-expressing tumor cells. This approach potentially enables KK2269 to exert activity locally while avoiding systemic toxicities mediated by CD40. The purpose of this work was to develop a pharmacokinetic-tumor target engagement model (PK-TE) using KK2269 nonclinical data and translation of the model to inform Phase 1 dosing scheme in humans.

Description of Methods & Materials: The PK-TE model development included: 1) serum concentrations of KK2269 from tumor- and non-tumor-bearing humanized CD40 (hCD40) mice and cynomolgus monkeys 2) the antitumor efficacy of KK2269 in mouse-EpCAM expressing B16F10 tumor-bearing hCD40 mice 3) in vitro Biacore binding affinities of KK2269 and 4) EpCAM and CD40 expressions on relevant cells. A mechanistic KK2269PK-TE model was developed using mice PK and antitumor activity data to understand the quantitative relationship among serum concentrations, tumor trimer concentrations, and TE for CD40 on DCs in tumors. The PK-TE model was translated to humans by translating the cynomolgus monkey PK to humans by allometric scaling. The tumor growth parameters for patients were informed using literature-based longitudinal tumor size data from NSCLC patients.

Data & Results: A 2-compartment PK model with two full -target mediated drug disposition (TMDD)- (CD40 and EpCAM) components well-described the PK data in mice and cynomolgus monkeys. A reasonable agreement was observed between the observed and the predicted serum PK and tumor growth data in mice by PK-TE model. The model predicted ~65% CD40 TE at tumor time to maximum concentration (Tmax) at a dose which yielded modest antitumor activity in mice. Additionally, the model predicted a dose-dependent increase followed by a saturation of the CD40 TE (~98% at tumor Tmax) at higher doses. The model also predicted bell shaped dose response with a decrease in antitumor activity at >100 mg/kg doses in mice. This model was translated to solid tumor subjects to inform the Phase 1 doses of KK2269 for monotherapy and combination studies with Docetaxel (NCT06266299). While the human starting dose was projected to target the CD40 TE at tumor Tmax equivalent to that simulated at a dose with modest antitumor activity in mice, the efficacious dose was projected to target the TE profile simulated at the efficacious dose in mice (near maximal antitumor activity and near maximal predicted TE (~97%) at tumor Tmax and TE was maintained above 50% for 75% of the dosing interval). The impact of varying starting tumor volumes and target expressions on the tumor TE were also studied.

Interpretation, Conclusion or Significance: A translational PK-TE model was successfully used to inform the Phase 1 dosing scheme for KK2269 in solid tumors. An integrated KK2269-PK-TE- immuno-oncology quantitative systems pharmacology (IO-QSP) model is being developed and validated to inform KK2269 Phase 2 doses/dosing regimen in combination with docetaxel.

Disclosures:

Citations/References: ^1, Vonderheide RH, Burg JM, Mick R, Trosko JA, Li D, Shaik MN, et al. Phase I study of the CD40 agonist antibody CP-870,893 combined with carboplatin and paclitaxel in patients with advanced solid tumors. Oncoimmunology. 2013;2(1), e23033.

Additional Information/Authors: Ragini Vuppugalla1, Krina Mehta1, Hidenori Takada2, Maiko Adachi2, Hiroyuki Ishida2, Munetoshi Ando2, Andrzej Kierzek3, Birses Debir3, Douglas Marsteller1, Matthew Hruska1
1 Kyowa Kirin Inc., Princeton, NJ
2 Kyowa Kirin Co., Ltd. Tokyo, Japan
3 Certara, UK