CD47, an ubiquitously expressed innate immune checkpoint receptor that serves as a universal "don't eat me" signal of phagocytosis, is often upregulated by hematologic and solid cancers to evade immune surveillance. Development of CD47-targeted modalities is hindered by the ubiquitous expression of the target, often leading to rapid drug elimination and hemotoxicity including anemia. To overcome such liabilities, we have developed a fully human bispecific antibody, NI-1701, designed to coengage CD47 and CD19 selectively on B cells. NI-1701 demonstrates favorable elimination kinetics with no deleterious effects seen on hematologic parameters following single or multiple administrations to nonhuman primates. Potent and activity is induced by NI-1701 to kill cancer cells across a plethora of B-cell malignancies and control tumor growth in xenograft mouse models. The mechanism affording maximal tumor growth inhibition by NI-1701 is dependent on the coengagement of CD47/CD19 on B cells inducing potent antibody-dependent cellular phagocytosis of the targeted cells. NI-1701-induced control of tumor growth in immunodeficient NOD/SCID mice was more effective than that achieved with the anti-CD20 targeted antibody, rituximab. Interestingly, a synergistic effect was seen when tumor-implanted mice were coadministered NI-1701 and rituximab leading to significantly improved tumor growth inhibition and regression in some animals. We describe herein, a novel bispecific antibody approach aimed at sensitizing B cells to become more readily phagocytosed and eliminated thus offering an alternative or adjunct therapeutic option to patients with B-cell malignancies refractory/resistant to anti-CD20-targeted therapy. .

The lack of draining lymphatic vessels in the central nervous system (CNS) contributes to the so-called "CNS immune privilege." However, despite such a unique anatomic feature, dendritic cells (DCs) are able to migrate from the CNS to cervical lymph nodes through a yet unknown pathway. In this report, labeled bone marrow-derived myeloid DCs were injected stereotaxically into the cerebrospinal fluid (CSF) or brain parenchyma of normal rats. We found that DCs injected within brain parenchyma migrate little from their site of injection and do not reach cervical lymph nodes. In contrast, intra-CSFinjected DCs either reach cervical lymph nodes or, for a minority of them, infiltrate the subventricular zone, where neural stem cells reside. Surprisingly, DCs that reach cervical lymph nodes preferentially IntroductionUnder normal conditions, the transport of immune cells from blood to the central nervous system (CNS) is restricted by 2 physical barriers: the blood-brain barrier formed by CNS parenchymal microvessels and the blood cerebrospinal fluid (CSF) barrier formed by the choroid plexuses. Also, the circulation of immune cells from brain to lymphoid organs is hampered by the lack of CNS-draining lymphatic vessels. Nevertheless, immune responses may develop in the CNS, and cervical lymph nodes are considered as major sites of antigen presentation during neuroinflammatory diseases. 1,2 Indeed, antigens are drained from the CNS to cervical lymph nodes along the axons of craniofacial peripheral nerves. 3,4 Also, it was reported that dendritic cells (DCs) are able to migrate out of the CNS and, in turn, to elicit a CNS-targeted immune response. 5,6 However, it is not clear whether DCs circulating out of the CNS actually migrate from brain parenchyma or from the CSF compartment. This point is of importance because DCs are absent from normal CNS parenchyma, 7 but they can be detected in CSF and in compartments associated with CSF circulation or production, including meninges and choroid plexuses. [8][9][10] Moreover, under neuroinflammatory conditions, DCs accumulate in the CSF 11,12 as well as in perivascular spaces, 13,14 anatomic compartments draining into the CSF. These findings, along with others, suggest that the CSF may be a major transport route for DCs circulating in the CNS and migrating either from CSF to CNS parenchyma or from CSF to the lymphoid organs. 11,12,15,16 In the present study, we tracked bone marrow-derived myeloid DCs injected stereotaxically into the CSF or brain parenchyma of rats under normal conditions. Materials and methods AnimalsAnimal care and procedures were conducted according to the guidelines approved by the French Ethical Committee (decree 87-848) and the European Community directive 86-609-EEC and meet the Neuroscience Society guidelines. The study protocol was approved by the ethical committee of Faculté de Médecine Laennec, Lyon, France. Eight-to 10-week-old female Sprague Dawley rats were obtained from Harlan (Gannat, France). ReagentsMurine GM-CSF, human Flt3-L, murine IL-4, and h...

Cannabinoids are potential agents for the development of therapeutic strategies against multiple sclerosis. Here we analyzed the role of the peripheral CB 2 cannabinoid receptor in the control of myeloid progenitor cell trafficking toward the inflamed spinal cord and their contribution to microglial activation in an animal model of multiple sclerosis (experimental autoimmune encephalomyelitis, EAE). CB 2 receptor knock-out mice showed an exacerbated clinical score of the disease when compared with their wild-type littermates, and this occurred in concert with extended axonal loss, T-lymphocyte (CD4 ؉ ) infiltration, and microglial (CD11b ؉ ) activation. Immature bone marrow-derived CD34 ؉ myeloid progenitor cells, which play a role in neuroinflammatory pathologies, were shown to express CB 2 receptors and to be abundantly recruited toward the spinal cords of CB 2 knock-out EAE mice. Bone marrow-derived cell transfer experiments further evidenced the increased contribution of these cells to microglial replenishment in the spinal cords of CB 2 -deficient animals. In line with these observations, selective pharmacological CB 2 activation markedly reduced EAE symptoms, axonal loss, and microglial activation. CB 2 receptor manipulation altered the expression pattern of different chemokines (CCL2, CCL3, CCL5) and their receptors (CCR1, CCR2), thus providing a mechanistic explanation for its role in myeloid progenitor recruitment during neuroinflammation. These findings demonstrate the protective role of CB 2 receptors in EAE pathology; provide evidence for a new site of CB 2 receptor action, namely the targeting of myeloid progenitor trafficking and its contribution to microglial activation; and support the potential use of non-psychoactive CB 2 agonists in therapeutic strategies for multiple sclerosis and other neuroinflammatory disorders.