A Novel Antibody-Drug Conjugate Targeting CCR7 in Hematologic Malignancies

Introduction:

CC-chemokine receptor 7 (CCR7) is expressed in lymphoid malignancies and is therefore an attractive target for antibody-drug conjugates (ADCs). JBH492 is a novel, CCR7-targeting ADC, comprised of a humanized anti-CCR7 IgG1 antibody, conjugated in a site-specific manner to the maytansinoid microtubule inhibitor DM4 via a cleavable linker.

Methods:

CCR7 expression was investigated in human and cynomolgus monkey normal tissue microarrays (TMA) by in situ hybridization (ISH). CCR7 expression across multiple malignancies was investigated by RNA sequencing (RNAseq). The cytotoxic ADC activity of JBH492 was evaluated in vitro in a CellTiter-Glo viability assay. To characterize the impact of the ADC on the CCL19/CCR7 axis, p-ERK was measured as a downstream signaling event of CCL19-mediated CCR7 pathway activation. The in vivo efficacy of JBH492 was investigated in multiple preclinical models of lymphoid malignancies, chosen to cover a range of various CCR7 expression levels, including a panel of 11 DLBCL patient derived xenograft (PDX) models. The safety of JBH492 was assessed in repeat dose toxicity studies conducted in cynomolgus monkeys.

Results:

RNAseq and flow cytometry reveal high CCR7 expression in lymphoid neoplasms, including chronic lymphocytic leukemia (CLL), B-cell and T-cell non-Hodgkin's lymphoma (NHL), with very limited expression in healthy tissues. Preclinical characterization of JBH492 demonstrates potent, target-dependent cytotoxic activity. In vitro binding studies support avidity-driven binding of JBH492 to CCR7-high tumor cells compared to CCR7-low healthy immune cells. Mechanistic studies of JBH492 suggest a dual mechanism of action, including payload-mediated cytotoxicity, and blockade of ligand-induced CCR7 signaling through antibody antagonistic functionality. In vivo studies showed robust and durable efficacy in multiple clinically relevant lymphoma models. JBH492 achieved PR or CR in 7/11 DLBCL PDX models (response rate ~64%). Nonclinical toxicology studies indicate a favorable safety profile with no notable changes in circulating immune cell populations.

Conclusions:

Our translational data support the hypothesis that JBH492 may have the potential to become a promising first-in-class ADC for the treatment of CCR7-expressing lymphoid malignancies. The first-in-human clinical trial in patients with refractory/relapsed CLL and non-Hodgkin's lymphoma is currently ongoing (NCT04240704).

Dang:Novartis Pharmaceuticals: Current Employment. Knee:Novartis Pharmaceuticals: Current Employment. Wang:Novartis Pharmaceuticals: Current Employment. Gao:Novartis Pharmaceuticals: Current Employment. Liu:Novartis Pharmaceuticals: Current Employment. Briones:Novartis Pharmaceuticals: Current Employment. Coulson:Novartis Pharmaceuticals: Current Employment. Makofske:Novartis Pharmaceuticals: Current Employment. Mansfield:Novartis Pharmaceuticals: Current Employment. Liu:Novartis Pharmaceuticals: Current Employment. Mulvey:Novartis Pharmaceuticals: Current Employment. Meseck:Novartis Pharmaceuticals: Current Employment, Current holder of stock options in a privately-held company. Woolfenden:Novartis Pharmaceuticals: Current Employment. Buchanan:Novartis Pharmaceuticals: Current Employment, Current equity holder in private company, Current equity holder in publicly-traded company, Current holder of stock options in a privately-held company. Steensma:Novartis Pharmaceuticals: Current Employment. Askoxylakis:Novartis Pharmaceuticals: Current Employment, Current equity holder in private company.