Abstract The homeostatic CC-chemokine receptor 7 (CCR7) is highly expressed in many hematological malignancies including chronic lymphocytic leukemia (CLL). CCR7 surface expression levels are much higher than those of CD20, and are correlated with poor prognosis. Upon engagement by its ligands (CCL19 and CCL21), CCR7 controls trafficking of CLL cells to locations where these chemokines are expressed, such as the lymph node (LN). In this protective microenvironment CCR7 ligands contribute to CLL cell survival and proliferation. Indeed, high CCR7-mediated in vitro migration of patient CLL cells correlates with LN involvement and adverse prognostic factors. Thus, strategies targeting CCR7 could provide an additional therapeutic approach for CLL. Therefore, we have generated CAP-100, the first humanized immunoglobulin G1 (IgG1) monoclonal antibody (mAb) that specifically binds to human CCR7 and neutralizes ligand-mediated signaling from both CCL19 and CCL21. The antibody effectively inhibited CLL cells migration and survival. Furthermore, in in vivo pre-clinical studies, CAP-100 was shown to inhibit entry of CCR7-expressing cells to LNs. The antibody showed potent cell killing activity against CLL cells while preserving normal blood cells. This Fc-mediated antibody-dependent cell-mediated cytotoxicity (ADCC) clearly outperformed standard-of-care in CLL, such as rituximab. ADCC and migration inhibition were both independent of prognostic markers for high risk CLL, such as TP53 mutation including 17p deletion and relapse/refractoriness to various standard therapies, including BTK-inhibitors. Finally, when given as monotherapy in disseminated NHL xenograft tumors in SCID mice, CAP-100 exhibited tumor growth inhibition in established tumors and provided significant survival. Collectively, our results demonstrate that CAP-100, the first-in-class anti-CCR7 mAb, is a potent antagonist with biological activity in CLL primary cells, including those from relapsed/refractory patients. Moreover, these results highlight the relevance of the CCR7-CCL19/CCL21 pathway as a therapeutic target in CLL. CAP-100’s unique propensity to block migration of CLL cells to the LN, in combination with its potent cell killing activity provides the biological rationale for use of CAP-100 in CLL, either as monotherapy or in combination with novel agents such as BTK-inhibitors. Clinical trials in CLL and other CCR7-expressing NHL will be initiated soon. Citation Format: Carlos Cuesta-Mateos, Cecilia Muñoz-Calleja, Javier Loscertales, Fernando Terron, Wim Mol. CAP-100: first-in-class anti-CCR7 antibody for CLL [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4849.