9631 Background: Histone deacetylase inhibitors represent a new class of targeted anticancer agen... more 9631 Background: Histone deacetylase inhibitors represent a new class of targeted anticancer agents. Deacetylation of histones by HDACs is postulated to inactivate tumor suppressor genes leading to neoplastic transformation. Thus, inhibition of these enzymes might restore normal growth control. Several HDAC inhibitors, including MGCD0103, are in clinical trials. Methods: To analyze the pharmacodynamic properties of MGCD0103 in Phase I clinical studies, we have used a variety of biological assays to monitor HDAC inhibitory activity. An HDAC enzyme assay using intact white cells from patients was used to monitor the enzyme inhibitory activity of MGCD0103, while histone acetylation in these cells was analyzed by Western blotting, fluorescence-activated cell sorting (FACS) and enzyme-linked immunosorbent assay (ELISA). Results: We demonstrate that, in 3 of the first 7 patients for whom comparative data are available, HDAC enzyme inhibition correlates positively with histone acetylation induction in their peri...
Trophoblast cell surface antigen-2 (TROP2) is a membrane-bound protein with an extracellular doma... more Trophoblast cell surface antigen-2 (TROP2) is a membrane-bound protein with an extracellular domain highly expressed in a wide range of late-stage epithelial cancers. TROP2 upregulation in solid cancers is associated with increased tumor aggressiveness, metastasis, and an overall decreased survival in large groups of difficult-to-treat cancers, making it an attractive target for cancer therapy. TROP2 positive cancers have been successfully targeted by antibody-drug conjugates (ADC) but not naked functional antibodies. ADC’s have associated drug toxicity in healthy tissues, off-target effects, and payload delivery issues. Given ADC dose-limiting side effects, narrow therapeutic windows, and efficacy limitations, there is a pressing need to improve anti-TROP2 therapeutics for patients who are poorly served by current therapies, if at all. Understanding these needs, we applied our proprietary heavy chain-only antibody (HCAb) transgenic mouse platform to the creation of therapeutic anti...
Trophoblast cell surface antigen-2 (TROP2) is a membrane-bound protein expressed during developme... more Trophoblast cell surface antigen-2 (TROP2) is a membrane-bound protein expressed during development and at lower levels in normal adult tissues. TROP2 has pleiotropic functions including formation of cell-cell junctions by mediating interactions with extracellular and intracellular proteins. In situations of TROP2 deficiency its role in normal tissues appears to be compensated by expression of EpCAM, a highly related family member. In cancer, the levels of TROP2 are increased in many epithelial tumor types. Overexpression of TROP2 confer oncogenic behavior in several in vitro and in vivo models. Both its extracellular and intracellular domains play a role in modulating interactions with ligands and/or receptors and with intracellular signaling partners to result in an oncogenic phenotype. In many solid tumors TROP2 upregulation is associated with increased tumor aggressiveness, metastasis, and decreased survival in large groups of difficult-to-treat cancers, making it an attractive ...
Targeting histone deacetylases (HDACs) is a new approach in human cancer therapy in recent years.... more Targeting histone deacetylases (HDACs) is a new approach in human cancer therapy in recent years. Currently several HDAC pan-inhibitors are in clinical trials, such as SAHA. We hypothesized that isotype-specific HDAC inhibitors will exhibit significant antitumor activity but have less ...
We developed a single domain VHH multi-specific antibody format. Multispecific antibodies have mu... more We developed a single domain VHH multi-specific antibody format. Multispecific antibodies have multiple mechanisms of action which may work independently or together, to achieve better clinical outcomes in cancers with high unmet medical need such as SCLC. Here we describe the preclinical development of a trispecific antibody (KB-436) that targets Dopamine Receptor 2 (DRD2), PD-1 and CD47. DRD2 is a G protein-coupled receptor upregulated in many cancer types where it correlates with decreased patient survival. In pre-clinical studies DRD2 is associated with cancer cell stemness and tumor growth. Clinical responses were achieved with small molecules targeting DRD2 and dopaminergic drugs. In SCLC, representing 15% of lung cancers, 60-70% of patients showed high expression of DRD2. Checkpoint inhibition has shown some efficacy in lung cancer where PD-L1 inhibitors were approved as first line therapy in SCLC . SCLC patients rapidly fail chemotherapy, develop resistance to treatment incl...
739 MGCD0103 is a novel non-hydroxamate histone deacetylase inhibitor which specifically targets ... more 739 MGCD0103 is a novel non-hydroxamate histone deacetylase inhibitor which specifically targets HDAC1, 2, 3 and 11. Previously, we have shown that MGCD0103 has broad-spectrum antitumor activities in preclinical animal models and its preliminary clinical activity has been shown in multiple Phase II trials in patients with relapsed or refractory Hodgkin’s lymphoma or Non-Hodgkin lymphoma , high-risk myelodysplastic syndrome (MDS) and acute myologenous leukemia (AML). To further understand the mechanism of action of MGCD0103, we investigated the anti-angiogenesis activity and specific components of the angiogenesis pathways that were modulated by MGCD0103. We found MGCD0103 significantly inhibits tubule growth of cultured human endothelial cells in a dose-dependent manner in vitro. In addition, MGCD0103 can induce transcription of an anti-angiogenesis factor, thrombospondin 1 (TSP-1), in human cancer cells in vitro independent of their tissue origins. Synergistic induction of TSP-1 wa...
MGCD265 is an oral multitargeted receptor tyrosine kinase inhibitor in Phase II clinical developm... more MGCD265 is an oral multitargeted receptor tyrosine kinase inhibitor in Phase II clinical development. MGCD265 targets the Met receptor tyrosine kinase and blocks Met activities which contribute to cancer development and progression such as cell proliferation, motility/invasion, angiogenesis and tumor cell survival. Although there is a large body of literature supporting Met activities as key to epithelial-mesenchymal transition and tumorigenesis, it is now accepted that the coordination of Met signaling with other regulators is central to oncogenesis. Met engages in cross-talks with several membrane proteins including the EGFR. Met and EGFR are coexpressed on tumor cells and functionally cooperate to amplify activating signals. Moreover, in NSCLC, Met gene amplification or overexpression of HGF, has been identified as a major molecular mechanism through which tumors evade EGFR inhibition by specific inhibitors such as gefitinib and erlotinib. Taken together, these studies provide a ...
Purpose: The pharmacodynamic properties of MGCD0103, an isotype-selective inhibitor of histone de... more Purpose: The pharmacodynamic properties of MGCD0103, an isotype-selective inhibitor of histone deacetylase (HDAC), were evaluated in preclinical models and patients with a novel whole-cell HDAC enzyme assay. Experimental Design: Boc-Lys(q-Ac)-AMC, a HDAC substrate with fluorescent readout, was found to be cell permeable and was used to monitor MGCD0103-mediated HDAC inhibition in cultured cancer cells in vitro, in peripheralWBC ex vivo, in mice in vivo, and in human patients. Results: MGCD0103 inhibited HDAC activity in several human cancer cell lines in vitro and in human peripheralWBC ex vivo in a dose-dependent manner. Unlike suberoylanilide hydroxamic acid, the HDAC inhibitory activity of MGCD0103 was time dependent and sustained for at least 24 hours following drug removal in peripheral WBC ex vivo. Inhibitory activity of MGCD0103 was sustained for at least 8 hours in vivo in mice and 48 hours in patients with solid tumors. HDAC inhibitory activity of MGCD0103 in peripheralWBC ...
MGCD0103, an orally available class I histone deacetylase (HDAC) inhibitor, was examined for pre‐... more MGCD0103, an orally available class I histone deacetylase (HDAC) inhibitor, was examined for pre‐clinical activity in chronic lymphocytic leukaemia (CLL). A phase II clinical trial was performed, starting at a dose of 85 mg/d, three times per week. Dose escalation to 110 mg or the addition of rituximab was permitted in patients without a response after two or more cycles. MGCD0103 demonstrated pre‐clinical activity against CLL cells with a LC50 (concentration lethal to 50%) of 0·23 μmol/l and increased acetylation of the HDAC class I specific target histone H3. Twenty‐one patients received a median of two cycles of MGCD0103 (range, 0–12). All patients had previously received fludarabine, 33% were fludarabine refractory, and 71% had del(11q22·3) or del(17p13·1). No responses according to the National Cancer Institutes 1996 criteria were observed. Three patients received 110 mg and four patients received concomitant rituximab, with no improvement in response. Grade 3–4 toxicity consis...
3039 Background: MGCD265 is a multikinase inhibitor, with nanomolar IC50 against Met, VEGFR 1, 2,... more 3039 Background: MGCD265 is a multikinase inhibitor, with nanomolar IC50 against Met, VEGFR 1, 2, and 3, Tie-2, and Ron. This spectrum may confer greater anti-tumor activity than inhibiting either target alone. MGCD265 has broad anti-tumor effects in preclinical models. Methods: Patients (pts) with advanced malignancies were enrolled in this Phase I, open-label, dose escalating study using the classic 3+3 study design. MGCD265 was administered every day over a 21-day cycle. The aim of this study is to determine the safety profile including the maximum tolerated dose and the dose limiting toxicities (DLTs) of MGCD265. The pharmacokinetic (PK), pharmacodynamic (PD) profiles and the anti-tumor activity of MGCD265 were also evaluated. Results: As of January 10, 2012, 56 patients were enrolled (M/F: 37/19; ECOG 0/1/2: 16/38/2; median age: 61 years old). MGCD265 was dose escalated from 24 mg/m2 QD to 235 mg/m2 BID with a favorable safety profile. The DLTs (n=1 for each event) captured wer...
9631 Background: Histone deacetylase inhibitors represent a new class of targeted anticancer agen... more 9631 Background: Histone deacetylase inhibitors represent a new class of targeted anticancer agents. Deacetylation of histones by HDACs is postulated to inactivate tumor suppressor genes leading to neoplastic transformation. Thus, inhibition of these enzymes might restore normal growth control. Several HDAC inhibitors, including MGCD0103, are in clinical trials. Methods: To analyze the pharmacodynamic properties of MGCD0103 in Phase I clinical studies, we have used a variety of biological assays to monitor HDAC inhibitory activity. An HDAC enzyme assay using intact white cells from patients was used to monitor the enzyme inhibitory activity of MGCD0103, while histone acetylation in these cells was analyzed by Western blotting, fluorescence-activated cell sorting (FACS) and enzyme-linked immunosorbent assay (ELISA). Results: We demonstrate that, in 3 of the first 7 patients for whom comparative data are available, HDAC enzyme inhibition correlates positively with histone acetylation induction in their peri...
Trophoblast cell surface antigen-2 (TROP2) is a membrane-bound protein with an extracellular doma... more Trophoblast cell surface antigen-2 (TROP2) is a membrane-bound protein with an extracellular domain highly expressed in a wide range of late-stage epithelial cancers. TROP2 upregulation in solid cancers is associated with increased tumor aggressiveness, metastasis, and an overall decreased survival in large groups of difficult-to-treat cancers, making it an attractive target for cancer therapy. TROP2 positive cancers have been successfully targeted by antibody-drug conjugates (ADC) but not naked functional antibodies. ADC’s have associated drug toxicity in healthy tissues, off-target effects, and payload delivery issues. Given ADC dose-limiting side effects, narrow therapeutic windows, and efficacy limitations, there is a pressing need to improve anti-TROP2 therapeutics for patients who are poorly served by current therapies, if at all. Understanding these needs, we applied our proprietary heavy chain-only antibody (HCAb) transgenic mouse platform to the creation of therapeutic anti...
Trophoblast cell surface antigen-2 (TROP2) is a membrane-bound protein expressed during developme... more Trophoblast cell surface antigen-2 (TROP2) is a membrane-bound protein expressed during development and at lower levels in normal adult tissues. TROP2 has pleiotropic functions including formation of cell-cell junctions by mediating interactions with extracellular and intracellular proteins. In situations of TROP2 deficiency its role in normal tissues appears to be compensated by expression of EpCAM, a highly related family member. In cancer, the levels of TROP2 are increased in many epithelial tumor types. Overexpression of TROP2 confer oncogenic behavior in several in vitro and in vivo models. Both its extracellular and intracellular domains play a role in modulating interactions with ligands and/or receptors and with intracellular signaling partners to result in an oncogenic phenotype. In many solid tumors TROP2 upregulation is associated with increased tumor aggressiveness, metastasis, and decreased survival in large groups of difficult-to-treat cancers, making it an attractive ...
Targeting histone deacetylases (HDACs) is a new approach in human cancer therapy in recent years.... more Targeting histone deacetylases (HDACs) is a new approach in human cancer therapy in recent years. Currently several HDAC pan-inhibitors are in clinical trials, such as SAHA. We hypothesized that isotype-specific HDAC inhibitors will exhibit significant antitumor activity but have less ...
We developed a single domain VHH multi-specific antibody format. Multispecific antibodies have mu... more We developed a single domain VHH multi-specific antibody format. Multispecific antibodies have multiple mechanisms of action which may work independently or together, to achieve better clinical outcomes in cancers with high unmet medical need such as SCLC. Here we describe the preclinical development of a trispecific antibody (KB-436) that targets Dopamine Receptor 2 (DRD2), PD-1 and CD47. DRD2 is a G protein-coupled receptor upregulated in many cancer types where it correlates with decreased patient survival. In pre-clinical studies DRD2 is associated with cancer cell stemness and tumor growth. Clinical responses were achieved with small molecules targeting DRD2 and dopaminergic drugs. In SCLC, representing 15% of lung cancers, 60-70% of patients showed high expression of DRD2. Checkpoint inhibition has shown some efficacy in lung cancer where PD-L1 inhibitors were approved as first line therapy in SCLC . SCLC patients rapidly fail chemotherapy, develop resistance to treatment incl...
739 MGCD0103 is a novel non-hydroxamate histone deacetylase inhibitor which specifically targets ... more 739 MGCD0103 is a novel non-hydroxamate histone deacetylase inhibitor which specifically targets HDAC1, 2, 3 and 11. Previously, we have shown that MGCD0103 has broad-spectrum antitumor activities in preclinical animal models and its preliminary clinical activity has been shown in multiple Phase II trials in patients with relapsed or refractory Hodgkin’s lymphoma or Non-Hodgkin lymphoma , high-risk myelodysplastic syndrome (MDS) and acute myologenous leukemia (AML). To further understand the mechanism of action of MGCD0103, we investigated the anti-angiogenesis activity and specific components of the angiogenesis pathways that were modulated by MGCD0103. We found MGCD0103 significantly inhibits tubule growth of cultured human endothelial cells in a dose-dependent manner in vitro. In addition, MGCD0103 can induce transcription of an anti-angiogenesis factor, thrombospondin 1 (TSP-1), in human cancer cells in vitro independent of their tissue origins. Synergistic induction of TSP-1 wa...
MGCD265 is an oral multitargeted receptor tyrosine kinase inhibitor in Phase II clinical developm... more MGCD265 is an oral multitargeted receptor tyrosine kinase inhibitor in Phase II clinical development. MGCD265 targets the Met receptor tyrosine kinase and blocks Met activities which contribute to cancer development and progression such as cell proliferation, motility/invasion, angiogenesis and tumor cell survival. Although there is a large body of literature supporting Met activities as key to epithelial-mesenchymal transition and tumorigenesis, it is now accepted that the coordination of Met signaling with other regulators is central to oncogenesis. Met engages in cross-talks with several membrane proteins including the EGFR. Met and EGFR are coexpressed on tumor cells and functionally cooperate to amplify activating signals. Moreover, in NSCLC, Met gene amplification or overexpression of HGF, has been identified as a major molecular mechanism through which tumors evade EGFR inhibition by specific inhibitors such as gefitinib and erlotinib. Taken together, these studies provide a ...
Purpose: The pharmacodynamic properties of MGCD0103, an isotype-selective inhibitor of histone de... more Purpose: The pharmacodynamic properties of MGCD0103, an isotype-selective inhibitor of histone deacetylase (HDAC), were evaluated in preclinical models and patients with a novel whole-cell HDAC enzyme assay. Experimental Design: Boc-Lys(q-Ac)-AMC, a HDAC substrate with fluorescent readout, was found to be cell permeable and was used to monitor MGCD0103-mediated HDAC inhibition in cultured cancer cells in vitro, in peripheralWBC ex vivo, in mice in vivo, and in human patients. Results: MGCD0103 inhibited HDAC activity in several human cancer cell lines in vitro and in human peripheralWBC ex vivo in a dose-dependent manner. Unlike suberoylanilide hydroxamic acid, the HDAC inhibitory activity of MGCD0103 was time dependent and sustained for at least 24 hours following drug removal in peripheral WBC ex vivo. Inhibitory activity of MGCD0103 was sustained for at least 8 hours in vivo in mice and 48 hours in patients with solid tumors. HDAC inhibitory activity of MGCD0103 in peripheralWBC ...
MGCD0103, an orally available class I histone deacetylase (HDAC) inhibitor, was examined for pre‐... more MGCD0103, an orally available class I histone deacetylase (HDAC) inhibitor, was examined for pre‐clinical activity in chronic lymphocytic leukaemia (CLL). A phase II clinical trial was performed, starting at a dose of 85 mg/d, three times per week. Dose escalation to 110 mg or the addition of rituximab was permitted in patients without a response after two or more cycles. MGCD0103 demonstrated pre‐clinical activity against CLL cells with a LC50 (concentration lethal to 50%) of 0·23 μmol/l and increased acetylation of the HDAC class I specific target histone H3. Twenty‐one patients received a median of two cycles of MGCD0103 (range, 0–12). All patients had previously received fludarabine, 33% were fludarabine refractory, and 71% had del(11q22·3) or del(17p13·1). No responses according to the National Cancer Institutes 1996 criteria were observed. Three patients received 110 mg and four patients received concomitant rituximab, with no improvement in response. Grade 3–4 toxicity consis...
3039 Background: MGCD265 is a multikinase inhibitor, with nanomolar IC50 against Met, VEGFR 1, 2,... more 3039 Background: MGCD265 is a multikinase inhibitor, with nanomolar IC50 against Met, VEGFR 1, 2, and 3, Tie-2, and Ron. This spectrum may confer greater anti-tumor activity than inhibiting either target alone. MGCD265 has broad anti-tumor effects in preclinical models. Methods: Patients (pts) with advanced malignancies were enrolled in this Phase I, open-label, dose escalating study using the classic 3+3 study design. MGCD265 was administered every day over a 21-day cycle. The aim of this study is to determine the safety profile including the maximum tolerated dose and the dose limiting toxicities (DLTs) of MGCD265. The pharmacokinetic (PK), pharmacodynamic (PD) profiles and the anti-tumor activity of MGCD265 were also evaluated. Results: As of January 10, 2012, 56 patients were enrolled (M/F: 37/19; ECOG 0/1/2: 16/38/2; median age: 61 years old). MGCD265 was dose escalated from 24 mg/m2 QD to 235 mg/m2 BID with a favorable safety profile. The DLTs (n=1 for each event) captured wer...
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