MP0250, A BISPECIFIC VEGF- AND HGF-BLOCKING MULTI-DARPIN*, IN COMBINATION WITH BORTEZOMIB IN MULTIPLE MYELOMA: PRECLINICAL RATIONALE AND PHASE 2 STUDY OUTLINE
(Abstract release date: 05/19/16)
EHA Library. Stumpp M. 06/09/16; 132834; E1285
Dr. Michael Stumpp
Contributions
Contributions
Abstract
Abstract: E1285
Type: Eposter Presentation
Background
Despite advances in the treatment of multiple myeloma (MM), there is no cure. Patients eventually relapse, requiring multiple lines of treatment. Upregulation of both the vascular endothelial growth factor (VEGF) and hepatocyte growth factor (HGF) pathways has been implicated in loss of response to therapy. VEGF and HGF are increasingly overexpressed with MM progression and have been linked to poor prognosis: they are known to be able to stimulate neovascularization, bone destruction, and myeloma proliferation, migration, and adhesion in the bone marrow. Preclinical studies have shown that refractory, high HGF-expressing MM cell lines can be re-sensitized to treatment by inhibiting HGF/cMET signaling. MP0250 is a bispecific VEGF / HGF blocking multi-DARPin which is currently in a phase 1 study in solid tumors.
Aims
We are presenting the preclinical rationale for using MP0250 in combination with bortezomib (BTZ) in a planned phase 2 study in MM patients.
Methods
MP0250 and BTZ, alone and in combination, were tested in an orthotopic murine xenograft model in which human MM cells were implanted in murine tibial bone marrow. Tumor growth and muscle invasion was monitored by caliper measurements and CT scans, and bone destruction was analyzed by X-ray and microCT. Ex vivo analysis included the determination of M protein levels.
Results
MP0250 significantly inhibited bone lysis (total and cortical bone volumes) and tumor invasion in a dose-dependent manner. In both the MP0250 and MP0250+BTZ groups, tumor infiltration into the tibial muscle was significantly reduced while BTZ alone had no effect. M protein was reduced and inhibition of bone lysis was increased when the combination of BTZ and MP0250 was compared to BTZ alone. The results show that blockade of HGF and VEGF by MP0250 on its own has a beneficial effect and that enhanced effects can be achieved in combination with BTZ.
Conclusion
MP0250, a multi-DARPin specifically blocking HGF and VEGF, improves the efficacy of BTZ in a preclinical MM model. Consequent to this and a favorable phase 1 study, MP0250 will be evaluated in a phase 2 study in MM in combination with BTZ+DEX. *DARPins are small repeat proteins, designed to bind targets with high specificity and potency, and which can be combined in a modular fashion.
Session topic: E-poster
Keyword(s): Bortezomib, Hepatocyte growth factor, Multiple myeloma, Vascular endothelial growth factor (VEGF)
Type: Eposter Presentation
Background
Despite advances in the treatment of multiple myeloma (MM), there is no cure. Patients eventually relapse, requiring multiple lines of treatment. Upregulation of both the vascular endothelial growth factor (VEGF) and hepatocyte growth factor (HGF) pathways has been implicated in loss of response to therapy. VEGF and HGF are increasingly overexpressed with MM progression and have been linked to poor prognosis: they are known to be able to stimulate neovascularization, bone destruction, and myeloma proliferation, migration, and adhesion in the bone marrow. Preclinical studies have shown that refractory, high HGF-expressing MM cell lines can be re-sensitized to treatment by inhibiting HGF/cMET signaling. MP0250 is a bispecific VEGF / HGF blocking multi-DARPin which is currently in a phase 1 study in solid tumors.
Aims
We are presenting the preclinical rationale for using MP0250 in combination with bortezomib (BTZ) in a planned phase 2 study in MM patients.
Methods
MP0250 and BTZ, alone and in combination, were tested in an orthotopic murine xenograft model in which human MM cells were implanted in murine tibial bone marrow. Tumor growth and muscle invasion was monitored by caliper measurements and CT scans, and bone destruction was analyzed by X-ray and microCT. Ex vivo analysis included the determination of M protein levels.
Results
MP0250 significantly inhibited bone lysis (total and cortical bone volumes) and tumor invasion in a dose-dependent manner. In both the MP0250 and MP0250+BTZ groups, tumor infiltration into the tibial muscle was significantly reduced while BTZ alone had no effect. M protein was reduced and inhibition of bone lysis was increased when the combination of BTZ and MP0250 was compared to BTZ alone. The results show that blockade of HGF and VEGF by MP0250 on its own has a beneficial effect and that enhanced effects can be achieved in combination with BTZ.
Conclusion
MP0250, a multi-DARPin specifically blocking HGF and VEGF, improves the efficacy of BTZ in a preclinical MM model. Consequent to this and a favorable phase 1 study, MP0250 will be evaluated in a phase 2 study in MM in combination with BTZ+DEX. *DARPins are small repeat proteins, designed to bind targets with high specificity and potency, and which can be combined in a modular fashion.
Session topic: E-poster
Keyword(s): Bortezomib, Hepatocyte growth factor, Multiple myeloma, Vascular endothelial growth factor (VEGF)
Abstract: E1285
Type: Eposter Presentation
Background
Despite advances in the treatment of multiple myeloma (MM), there is no cure. Patients eventually relapse, requiring multiple lines of treatment. Upregulation of both the vascular endothelial growth factor (VEGF) and hepatocyte growth factor (HGF) pathways has been implicated in loss of response to therapy. VEGF and HGF are increasingly overexpressed with MM progression and have been linked to poor prognosis: they are known to be able to stimulate neovascularization, bone destruction, and myeloma proliferation, migration, and adhesion in the bone marrow. Preclinical studies have shown that refractory, high HGF-expressing MM cell lines can be re-sensitized to treatment by inhibiting HGF/cMET signaling. MP0250 is a bispecific VEGF / HGF blocking multi-DARPin which is currently in a phase 1 study in solid tumors.
Aims
We are presenting the preclinical rationale for using MP0250 in combination with bortezomib (BTZ) in a planned phase 2 study in MM patients.
Methods
MP0250 and BTZ, alone and in combination, were tested in an orthotopic murine xenograft model in which human MM cells were implanted in murine tibial bone marrow. Tumor growth and muscle invasion was monitored by caliper measurements and CT scans, and bone destruction was analyzed by X-ray and microCT. Ex vivo analysis included the determination of M protein levels.
Results
MP0250 significantly inhibited bone lysis (total and cortical bone volumes) and tumor invasion in a dose-dependent manner. In both the MP0250 and MP0250+BTZ groups, tumor infiltration into the tibial muscle was significantly reduced while BTZ alone had no effect. M protein was reduced and inhibition of bone lysis was increased when the combination of BTZ and MP0250 was compared to BTZ alone. The results show that blockade of HGF and VEGF by MP0250 on its own has a beneficial effect and that enhanced effects can be achieved in combination with BTZ.
Conclusion
MP0250, a multi-DARPin specifically blocking HGF and VEGF, improves the efficacy of BTZ in a preclinical MM model. Consequent to this and a favorable phase 1 study, MP0250 will be evaluated in a phase 2 study in MM in combination with BTZ+DEX. *DARPins are small repeat proteins, designed to bind targets with high specificity and potency, and which can be combined in a modular fashion.
Session topic: E-poster
Keyword(s): Bortezomib, Hepatocyte growth factor, Multiple myeloma, Vascular endothelial growth factor (VEGF)
Type: Eposter Presentation
Background
Despite advances in the treatment of multiple myeloma (MM), there is no cure. Patients eventually relapse, requiring multiple lines of treatment. Upregulation of both the vascular endothelial growth factor (VEGF) and hepatocyte growth factor (HGF) pathways has been implicated in loss of response to therapy. VEGF and HGF are increasingly overexpressed with MM progression and have been linked to poor prognosis: they are known to be able to stimulate neovascularization, bone destruction, and myeloma proliferation, migration, and adhesion in the bone marrow. Preclinical studies have shown that refractory, high HGF-expressing MM cell lines can be re-sensitized to treatment by inhibiting HGF/cMET signaling. MP0250 is a bispecific VEGF / HGF blocking multi-DARPin which is currently in a phase 1 study in solid tumors.
Aims
We are presenting the preclinical rationale for using MP0250 in combination with bortezomib (BTZ) in a planned phase 2 study in MM patients.
Methods
MP0250 and BTZ, alone and in combination, were tested in an orthotopic murine xenograft model in which human MM cells were implanted in murine tibial bone marrow. Tumor growth and muscle invasion was monitored by caliper measurements and CT scans, and bone destruction was analyzed by X-ray and microCT. Ex vivo analysis included the determination of M protein levels.
Results
MP0250 significantly inhibited bone lysis (total and cortical bone volumes) and tumor invasion in a dose-dependent manner. In both the MP0250 and MP0250+BTZ groups, tumor infiltration into the tibial muscle was significantly reduced while BTZ alone had no effect. M protein was reduced and inhibition of bone lysis was increased when the combination of BTZ and MP0250 was compared to BTZ alone. The results show that blockade of HGF and VEGF by MP0250 on its own has a beneficial effect and that enhanced effects can be achieved in combination with BTZ.
Conclusion
MP0250, a multi-DARPin specifically blocking HGF and VEGF, improves the efficacy of BTZ in a preclinical MM model. Consequent to this and a favorable phase 1 study, MP0250 will be evaluated in a phase 2 study in MM in combination with BTZ+DEX. *DARPins are small repeat proteins, designed to bind targets with high specificity and potency, and which can be combined in a modular fashion.
Session topic: E-poster
Keyword(s): Bortezomib, Hepatocyte growth factor, Multiple myeloma, Vascular endothelial growth factor (VEGF)
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