S897 VALIDATION OF A NOVEL MECHANISM OF ACTION FOR TREATMENT OF CCR7+ HEMATOLOGICAL MALIGNANCIES WITH FIRST‐IN‐CLASS ANTIBODY CAP‐100
Authors: C. Cuesta‐Mateos, R. Juarez‐Sánchez, T. Mateu‐Albero, C. Muñoz‐Calleja, J. Loscertales, F. Terrón, M. Wim
Journal: HemaSphere (2019)

Background: The homeostatic CC‐chemokine receptor 7 (CCR7) controls trafficking of immune cells to the lymph node (LN). Accordingly, CCR7 is highly expressed in hematological malignancies with nodal involvement including chronic lymphocytic leukemia (CLL), several B‐cell non‐Hodgkin lymphomas (NHL) such as mantle cell lymphoma (MCL), and various mature T‐cell neoplasia like T‐cell prolymphocytic leukemia (T‐PLL) and Sézary syndrome (SS). Upon engagement by its ligands, the chemokines CCL19 and CCL21, CCR7 directs tumor cells to LN. In this protective microenvironment, CCR7 contributes to tumor cell survival and proliferation. Indeed, both high CCR7 surface expression levels and high CCR7‐triggered migratory responses correlate with lymphadenopathy, adverse prognostic factors, and shorter patient survival. Therefore, strategies targeting CCR7 could provide a novel therapeutic approach for CCR7 + hematological malignancies. Aims: In this study we aimed to validate CCR7 as a novel target for antibody‐based therapies in CCR7‐expressing blood cancers. Methods: We have generated CAP‐100, the first humanized IgG1 monoclonal antibody (mAb) that specifically binds to human CCR7 and neutralizes ligand‐mediated signaling, and evaluated the antibody in various in‐vitro and in‐vivo preclinical models. Results: CAP‐100 potently inhibited in vitro migration of primary CLL, MCL, T‐PLL and SS tumor cells. Furthermore, in vivo pre‐clinical studies confirmed that CAP‐100 effectively blocked entry of CCR7‐expressing cells to LNs. CAP‐100 also abrogated survival elicited by CCR7 in CLL, and showed potent antibody‐dependent cell‐mediated cytotoxicity (ADCC) against CLL or CCR7 + T‐lymphomas cells. This Fc‐mediated cell killing activity clearly outperformed anti‐CD20 mAb rituximab and anti‐CD52 mAb alemtuzumab, standards of care in B‐cell and T‐cell lymphomas respectively. In all cases, CAP‐100 activity was independent of prognostic markers for high risk disease. Finally, when given as monotherapy in disseminated B‐NHL and CLL xenograft tumors in SCID mice, CAP‐100 inhibited tumor growth and extended survival significantly. In addition, CAP‐100 strongly inhibited the infiltration into as well as the survival of tumor cells in the LN. Summary/Conclusion: Our results demonstrate that CAP‐100, the first‐in‐class anti‐CCR7 mAb, is a potent antagonist with biological activity in several CCR7 + hematological malignancies, including relapsed/refractory disease. Moreover, these results highlight the relevance of the CCR7‐CCL19/CCL21 pathway as a therapeutic target in these diseases. CAP‐100's unique ability to block migration of tumor cells to the LN (where also inhibits tumor cell survival), in combination with its potent cell killing activity, represents a novel and differentiating mechanism of action. This provides the biological rationale for use of CAP‐100, either as monotherapy or in combination with novel agents. Clinical trials in CLL and CCR7‐expressing NHL will be initiated soon.