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Anti-Eltd1 Monoclonal Antibody Therapy

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Anti-Eltd1 Monoclonal Antibody Therapy ANTI-ELTD1 MONOCLONAL ANTIBODY THERAPY ELTD1 Epidermal growth factor, Latrophilin and seven-transmembrane domain- containing 1 • Highly expressed in vascular endothelial and smooth muscle cells Favara DM et al., Biochem Soc Trans 2014; 42: 1658-64. Glioblastoma Multiforme (GBM) Background Available Treatment • Cancer of the brain or spinal cord • Surgical resection; • Tumors arise from cell types with neural • Radiation with temozolomide (TMZ); stem cell-like properties • Adjuvant chemotherapy with temozolomide • Typically very aggressive tumors (TMZ) • Treatment options are poor • Upon recurrence, bevacizumab (humanized VEGF mAb) has been approved to treat GBM Bevacizumab • Approved in 2009 as a second line treatment for GBM • Humanized Vascular Endothelial Growth Factor monoclonal antibody (VEGF mAb) • Anti-angiogenic treatment i.e. “tumor starving” • Side effects include hemorrhage, blood clots, and GI perforation ELTD1 is associated with VEGFR2 Endothelial Cells Glioma Cells ELTD1 (red), VEGFR2 (green) ELTD1 is a IHC Biomarker for High-Grade Gliomas ELTD1 is highly expressed in high-grade gliomas ELTD1 is associated with angiogenesis 50 HGG patients, 25 low-grade glioma patients. (HG) ELTD1 (red), CD31 (endothelial cells; green) High Grade (LG) Low Grade Towner et al., Neurosurgery, 2013. Anti-VEGF Ab treatment reduced expression of ELTD1 & VEGF (IHC) n=5 OMRF used a commercially available Polyclonal Ab against ELTD1 in our proof of concept studies Polyclonal Anti-ELTD1 Treatment Significantly Reduces Expression of ELTD1 and VEGFR2 (IHC) Data suggests that ELTD1 pAb treatment is targeting the tumor more effectively i.e VEGF Receptor and ELTD1 on the tumor surface than VEGF mAb treatment that targets the ligand (VEGF) and the tumor (ELTD1) Orthotopic GBM Models • Human G55 xenograft model has many attributes associated with human GBM, and is of high interest for angiogenesis studies Human G55 xenograft in nude mouse Stereotaxic orthotopic intracerebral implantation of cells 7.0 Tesla Small Animal MRI Polyclonal Anti-ELTD1 Antibody Therapy does not cause Hemorrhaging G55 UT Anti-ELTD1 Anti-VEGF n=5 Anti-ELTD1 antibody therapy does not cause hemorrhaging, as seen in anti-VEGF treatment Ziegler et al., Neuro Oncol, 2017. OMRF developed a proprietary monoclonal Ab against ELTD1, which is the therapeutic candidate for further development and humanization Anti-ELTD1 Monoclonal Antibody Therapy: Human G55 Gliomas Tumor Volumes: Targeting ELTD1 with a mAb is effective in a G55 orthotopic glioma model (human G55 xenograft) Anti-ELTD1 antibody therapy (optimized monoclonal) is more effective than the pAb (non-optimized polyclonal) Anti-ELTD1 Monoclonal Antibody Therapy: Human G55 Gliomas Survival: Targeting ELTD1 with a mAb is effective in a G55 orthotopic glioma model (human G55 xenograft) Anti-ELTD1 antibody therapy (optimized monoclonal) is more effective than the pAb (non-optimized polyclonal) pAb anti-ELTD1 treatment was not found to be as effective in a G55 tumor model, Anti-ELTD1 Antibody Therapy Decreases Microvascularity mAb Anti-ELTD1 therapy is more effective at decreasing micro-vascularity than pAb therapy, as measured by perfusion MRI (relative cerebral blood flow [rCBF]) mAb Anti-ELTD1 restores vascularity to normal Anti-ELTD1 Antibody Therapy Decreases Hemorrhaging Untreated Polyclonal 20X 20X Monoclonal Avastin 20X 20X mAb Anti-ELTD1 therapy is more effective at decreasing hemorrhaging than Avastin, as measured by histological iron staining. Avastin causes hemorrhaging. mAb Anti-ELTD1 has no associated hemorrhaging Anti-ELTD1 Antibody Therapy Decreases Notch mAb Anti- UT pAb ELTD1 therapy is more 20X 20X effective at mAb Normal decreasing Notch than Avastin, as measured by 20X 20X IHC staining. Avastin 20X Avastin has no effect on Notch levels. mAb Anti-ELTD1 restores Notch levels to normal (contralateral) Summary: Anti-ELTD1 Therapy Anti-ELTD1 monoclonal antibody therapy: Is effective in a highly aggressive (G55) orthotopic rodent xenograft model of GBM Reduces tumor volumes Increases animal survival Decreases microvascularity Decreases tumor Notch levels Decreased microvascularity indicate: ELTD1 treatment is anti-angiogenic (similar to VEGF mAb) Unlike anti-VEGF treatments, tumor vasculature returns to normal suggesting that the tumor microenvironment is altered Unlike bevacizumab (VEGF mAb), using an antibody against ELTD1 doesn't cause hemorrhage (either pAb or mAb) Anti-ELTD1 mAb could also treat other types of cancers Next Steps Scientific: • Further studies planned in using scFV fragment of mAb: • Molecular-targeted MRI to assess binding affinity • Efficacy • Survival • Tumor volumes • Microvasculature (perfusion imaging, MVD) MR image of a G55 tumor-bearing Molecular-targeted MRI with mAb for ELTD1 xenograft mouse MR image of a G55 tumor-bearing xenograft Molecular-targeted MRI with scFV-mAb for mouse ELTD1 SA-HRP 20X H&E 20X SA-HRP 20X H&E 20X Anti-ELTD1 Antibody scFv Fragment has High Binding Affinity in G55 GBM Tumor MRI probe either has mAb, pAb or scFv fragment or non- of mAb, or specific IgG non-specific IgG bound to MRI contrast agent construct mAb Anti-ELTD1 scFv fragment effectively binds to a G55 GBM tumor in a mouse xenograft model mAb Anti-ELTD1 scFv fragment binds to GBM tumors Anti-ELTD1 Antibody scFv Fragment has High Binding Affinity in G55 GBM Tumor Binding affinity kinetics MRI probe either has mAb, pAb or scFv fragment of mAb, or non-specific IgG bound to MRI contrast agent construct mAb Anti-ELTD1 scFv fragment effectively binds to a G55 GBM tumor in a mouse xenograft model mAb Anti-ELTD1 scFv fragment binds to GBM tumors effectively Anti-ELTD1 mAb Fragment Therapy: Human G55 Gliomas Survival: Targeting ELTD1 with a mAb fragment is effective in a G55 orthotopic glioma model (human G55 xenograft) Anti-ELTD1 antibody therapy (optimized mAB fragment) is more effective than the pAb (non- optimized polyclonal) mAb fragment anti-ELTD1 treatment was found to be as effective as full mAb in a G55 tumor model Anti-ELTD1 mAb Fragment Therapy: Human G55 Gliomas Tumor Volumes: Targeting ELTD1 with a mAb fragment seems to be effective in a G55 orthotopic glioma model (human G55 xenograft), but was not significant Anti-ELTD1 antibody therapy (optimized mAb fragment) shows a decreasing trend to be effective in reducing tumor volumes, but due to low animal no., was not significant, compared to UT Anti-ELTD1 mAb Fragment Therapy Decreases Microvascularity mAb fragment Anti-ELTD1 therapy is as effective at decreasing micro-vascularity as pAb therapy, as measured by perfusion MRI (relative cerebral blood flow [rCBF]) mAb fragment Anti-ELTD1 restores vascularity to near normal Next Steps Scientific: • Preliminary data (RNA seq) suggest that ELTD1 treatment could help address other disease indications (MS, ophthalmic conditions, other cancers, wound healing etc) by impacting known genetic pathways implicated in these diseases • Further studies planned in: • Multiple Sclerosis (refractory MS) • Ophthalmology indications: AMD & Retinopathy • Other cancers • Wound healing & anti-hemorrhage Business: • Collaborate with a commercialization partner/investor to advance the asset Next Steps Multiple Sclerosis (MS) – mouse EAE (experimental autoimmune encephomyelitis) model or non- specific IgG ng i nd i 1 b D T L mAb Anti-ELTD1 MRI probe efficiently binds to various E brain regions in an EAE mouse model for MS, compared to non-selective control MRI contrast agent ELTD1 levels are elevated in EAE mice Next Steps Multiple Sclerosis (MS) – mouse EAE (experimental autoimmune encephomyelitis) model 20X 20X Molecular-targeted MR imaging for Immunohistochemistry staining for ELTD1 (streptavidin-HRP binds to biotin ELTD1 moiety of anti-ELTD1 probe) mAb Anti-ELTD1 MRI probe efficiently binds to endothelial cells in brain of an EAE mouse model for MS Immunohistochemistry staining for ELTD1 indicates high levels in endothelial cells of EAE mouse ELTD1 levels are elevated in EAE mice APPENDIX RNA seq. data and other disease indications mAb Anti-ELTD1 Therapy Gene-Fold Changes: 15 Down-regulated >2-fold 7 Upregulated >2-fold Possible MOA Anti-angiogenic Gene Protein Gene Protein SCN5A Sodium channel protein NTSR1 neurotensin receptor 1 • BMP2 is pro-angiogenic type 5 subunit alpha BGLAP bone gamma- and increases vascular ADA Adenosine deaminase carboxyglutamate (gla) density CHRNA1 cholinergic receptor protein • APLN promotes nicotinic alpha 1 subunit MATN2 matrilin 2 angiogenesis, and may be L1CAM L1 cell adhesion CD74 CD74 molecule, major associated with TMZ Anti-ELTD1 molecule histocompatibility resistance F2RL3 coagulation factor II complex, class II invariant (thrombin) receptor-like chain • Inhibition of L1CAM 3 SLC14A1 solute carrier family 14 normalizes vasculature ASS1 argininosuccinate (urea transporter), • Decrease of VWA1 in EC synthase 1 member 1 (Kidd blood results in dysfunctional PCDH19 protocadherin 19 group) angiogenesis NCAM1 neural cell adhesion IKZF1 IKAROS family zinc finger 1 Effect on cell motility molecule 1 (Ikaros) • PRICKLE 1 plays a role in stanniocalcin 2 VWA1 von Willebrand factor A STC2 tumor cell motility; APLN apelin domain containing 1 SPNS2 spinster homolog 2 negative regulator of wnt BMP2 bone morphogenetic Effect on cell growth protein 2 • L1CAM required for growth ZNF469 zinc finger protein 469 of CD133+ glioma cells MME membrane metallo- endopeptidase PRICKLE1 prickle homolog 1 mAb Anti-ELTD1 Therapy Gene-Fold Changes: Down-regulated >2-fold MS Implications Gene >2-fold Protein
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