Contributions
Abstract: P871
Type: Poster Sessions
Abstract Category: Therapy - Immunomodulation/Immunosuppression
Background and goals: In multiple sclerosis (MS), blood-borne monocytes constitute a part of the central nervous system (CNS)-infiltrating cells and are paramount for promoting myelin degradation. Therefore, inhibiting monocyte migration to the CNS of MS patients could have a therapeutic benefit. We previously identified MOSPD2 (Motile sperm domain-containing protein 2) as a protein which is predominantly expressed on the surface of human monocytes and is essential for their migration. In this study, we assessed the potential of MOSPD2 as a target for treating CNS inflammation, using experimental autoimmune encephalomyelitis (EAE) as a test model.
Experimental procedure: MOSPD2 knockout (KO) mice were generated by introducing the MOSPD2-targeting construct to embryonic stem cells via homologous recombination. Anti-MOSPD2 monoclonal antibodies (mAbs) were prepared by immunizing mice with the extracellular region of human MOSPD2 and isolating hybridoma producing antibodies. EAE was induced by immunizing mice with myelin oligodendrocyte glycoprotein (MOG) peptide 35-55 emulsified in complete Freund's adjuvant and pertussis toxin.
Results: MOSPD2 KO mice showed attenuated release of monocytes from the bone-marrow, accompanied by reduced frequency of peripheral monocytes. Upon immunization with pMOG35-55, EAE development in MOSPD2 KO mice was suppressed. Pathological examination demonstrated that infiltration of monocytes and T-cells to the CNS was markedly reduced. Two mAbs, VBL-632 and VBL-634, significantly inhibited migration of monocytes in-vitro. Binding strength analysis showed that VBL-632 and VBL-634 feature KD at the range of 10-9-10-10M with VBL-634 maintaining a higher binding affinity to MOSPD2 than VBL-632. When employed in a prophylactic regimen, VB-632 and VB-634 profoundly inhibited EAE development. More importantly, VB-634 ameliorated disease severity even when administered during peak EAE.
Conclusions: The results indicate that MOSPD2 is essential for EAE pathogenesis, and that targeting MOSPD2 using mAbs may holds promise as a remedy for MS through inhibition of monocytes accumulation in the CNS.
Disclosure: All authors are employees and stock option holders of VBL Therapeutics.
Abstract: P871
Type: Poster Sessions
Abstract Category: Therapy - Immunomodulation/Immunosuppression
Background and goals: In multiple sclerosis (MS), blood-borne monocytes constitute a part of the central nervous system (CNS)-infiltrating cells and are paramount for promoting myelin degradation. Therefore, inhibiting monocyte migration to the CNS of MS patients could have a therapeutic benefit. We previously identified MOSPD2 (Motile sperm domain-containing protein 2) as a protein which is predominantly expressed on the surface of human monocytes and is essential for their migration. In this study, we assessed the potential of MOSPD2 as a target for treating CNS inflammation, using experimental autoimmune encephalomyelitis (EAE) as a test model.
Experimental procedure: MOSPD2 knockout (KO) mice were generated by introducing the MOSPD2-targeting construct to embryonic stem cells via homologous recombination. Anti-MOSPD2 monoclonal antibodies (mAbs) were prepared by immunizing mice with the extracellular region of human MOSPD2 and isolating hybridoma producing antibodies. EAE was induced by immunizing mice with myelin oligodendrocyte glycoprotein (MOG) peptide 35-55 emulsified in complete Freund's adjuvant and pertussis toxin.
Results: MOSPD2 KO mice showed attenuated release of monocytes from the bone-marrow, accompanied by reduced frequency of peripheral monocytes. Upon immunization with pMOG35-55, EAE development in MOSPD2 KO mice was suppressed. Pathological examination demonstrated that infiltration of monocytes and T-cells to the CNS was markedly reduced. Two mAbs, VBL-632 and VBL-634, significantly inhibited migration of monocytes in-vitro. Binding strength analysis showed that VBL-632 and VBL-634 feature KD at the range of 10-9-10-10M with VBL-634 maintaining a higher binding affinity to MOSPD2 than VBL-632. When employed in a prophylactic regimen, VB-632 and VB-634 profoundly inhibited EAE development. More importantly, VB-634 ameliorated disease severity even when administered during peak EAE.
Conclusions: The results indicate that MOSPD2 is essential for EAE pathogenesis, and that targeting MOSPD2 using mAbs may holds promise as a remedy for MS through inhibition of monocytes accumulation in the CNS.
Disclosure: All authors are employees and stock option holders of VBL Therapeutics.