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Three semimechanistic pharmacokinetic/pharmacodynamic (PK/PD) models, Simeoni, Jumbe, and Hybrid, were used for the efficacy translation of RC88 from preclinical to clinical. RC88 is a mesothelin‐targeting antibody–drug conjugate for malignant solid tumor. In the preclinical study, the relationship between PKs and PDs was determined using the xenograft mouse model derived from ovarian cancer and lung cancer cell lines. A secondary parameter representing the efficacy index of the drug, termed as tumor static concentration (TSC), was calculated using the three semimechanistic PK/PD models. A mechanism‐based target‐mediated drug disposition model was used to predict the human PKs. TSC from mice and predicted human PK were integrated to predict human efficacy dose. Results showed that 2 cell lines were sensitive to drugs, and the predicted efficacy dose was between 0.82 and 1.96 mg/kg q1w. [ABSTRACT FROM AUTHOR]

Abstract: Endometriosis affects women of reproductive age via unclear immunological mechanism(s). Myeloid‐derived suppressor cells (MDSCs) are a heterogeneous group of myeloid cells with potent immunosuppressive and angiogenic properties. Here, we found MDSCs significantly increased in the peripheral blood of patients with endometriosis and in the peritoneal cavity of a mouse model of surgically induced endometriosis. Majority of MDSCs were granulocytic, produced ROS, and arginase, and suppressed T‐cell proliferation. Depletion of MDSCs by antiGr‐1 antibody dramatically suppressed development of endometrial lesions in mice. The chemokines CXCL1, 2, and 5 were expressed at sites of lesion while MDSCs expressed CXCR‐2. These CXC‐chemokines promoted MDSC migration toward endometriotic implants both in vitro and in vivo. Also, CXCR2‐deficient mice show significantly decreased MDSC induction, endometrial lesions, and angiogenesis. Importantly, adoptive transfer of MDSCs into CXCR2‐KO mice restored endometriotic growth and angiogenesis. Together, this study demonstrates that MDSCs play a role in the pathogenesis of endometriosis and identifies a novel CXC‐chemokine and receptor for the recruitment of MDSCs, thereby providing a potential target for endometriosis treatment. [ABSTRACT FROM AUTHOR]