e19008 Background: CCR7 is highly expressed in many hematological malignancies including CLL, several B-cell non-Hodgkin lymphomas (NHL), and various T-cell neoplasias with nodal involvement. Upon engagement by its ligands (CCL19 and CCL21), CCR7 controls trafficking of cells to locations where these chemokines are expressed, such as the lymph node (LN) and central nervous system. In these protective microenvironments CCR7 ligands contribute to tumor cell survival and proliferation. Indeed, both high CCR7 surface expression levels and high migratory responses to CCR7 ligands correlate with LN involvement, adverse prognostic factors, and shorter patient survival. Thus, strategies targeting CCR7 could provide a novel therapeutic approach for CCR7+ hematological malignancies. Methods: 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, and evaluated the antibody in various in-vitro and in-vivo preclinical models. Results: CAP-100 effectively inhibited in vitro migration of primary patient samples of CLL, B-cell NHLs and T-cell neoplasias such as T-PLL or T-ALL. Furthermore, in in vivo pre-clinical studies, CAP-100 was shown to inhibit entry of CCR7-expressing cells to LNs. CAP-100 also abrogated survival elicited by CCR7 in CLL, and showed potent cell killing activity against CLL or CCR7+ T-lymphomas cells. This Fc-mediated antibody-dependent cell-mediated cytotoxicity (ADCC) clearly outperformed anti-CD20 or anti-CD52 standard-of-care antibodies in B-NHL and T-lymphomas respectively. In all cases, ADCC and migration inhibition were both 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 exhibited tumor growth inhibition and extended survival significantly. Conclusions: 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 propensity to block migration of tumor cells to the LN, in combination with its potent cell killing activity 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.
Allele-specific cancer cell killing in vitro and in vivo targeting a single-nucleotide polymorphism in POLR2A
