Research Interests:
SGN-B7H4V is a novel investigational antibody-drug conjugate composed of a B7-H4-directed human monoclonal antibody conjugated to the validated vedotin drug linker, which incorporates the microtubule disrupting agent monomethyl auristatin... more
SGN-B7H4V is a novel investigational antibody-drug conjugate composed of a B7-H4-directed human monoclonal antibody conjugated to the validated vedotin drug linker, which incorporates the microtubule disrupting agent monomethyl auristatin E (MMAE) via a protease-cleavable peptide linkage. This vedotin drug linker system has been clinically validated by multiple ADC programs, including brentuximab vedotin, enfortumab vedotin, tisotumab vedotin, and polatuzumab vedotin. B7-H4 is an immune checkpoint ligand with elevated expression on a variety of solid tumor types, including breast, ovarian, and endometrial tumors. SGN-B7H4V is designed to bind and internalize the B7-H4/ADC complex from the surface of malignant cells and release the cytotoxic payload MMAE. The antitumor activity of SGN-B7H4V may be multimodal as SGN-B7H4V can induce tumor cell death through several mechanisms, including MMAE-mediated direct cytotoxicity and bystander killing as well as antibody-mediated functions incl...
Research Interests:
The integrins are a large family of cell surface receptors with diverse roles in cellular adhesion, motility, and cytokinesis. Functional integrins exist as heterodimers consisting of single alpha and beta chains. Within this family,... more
The integrins are a large family of cell surface receptors with diverse roles in cellular adhesion, motility, and cytokinesis. Functional integrins exist as heterodimers consisting of single alpha and beta chains. Within this family, integrin beta-6, which dimerizes exclusively with isoform alpha-v, is expressed constitutively at low levels in numerous epithelial tissues and induced by tissue injury due to its role in tissue remodeling and wound repair. Numerous solid tumors, including non-small cell lung cancer (NSCLC), have been reported to overexpress integrin beta-6. Its role in tissue remodeling is believed to be the function that malignant cells exploit through its overexpression, allowing them to become more invasive into surrounding healthy tissue. Integrin beta-6 has also been reported to be among the integrins that can promote the epithelial to mesenchymal transition as well as provide resistance to anoikis, thus increasing the metastatic potential of malignant cells expre...
Research Interests:
Interleukin-1 (IL-1) has multiple functions in both the periphery and the central nervous system (CNS) and is regulated at many levels. We identified an isoform of the IL-1 receptor (IL-1R) accessory protein (termed AcPb) that is... more
Interleukin-1 (IL-1) has multiple functions in both the periphery and the central nervous system (CNS) and is regulated at many levels. We identified an isoform of the IL-1 receptor (IL-1R) accessory protein (termed AcPb) that is expressed exclusively in the CNS. AcPb interacted with IL-1 and the IL-1R but was unable to mediate canonical IL-1 responses. AcPb expression, however, modulated neuronal gene expression in response to IL-1 treatment in vitro. Animals lacking AcPb demonstrated an intact peripheral IL-1 response and developed experimental autoimmune encephalomyelitis (EAE) similarly to wild-type mice. AcPb-deficient mice were instead more vulnerable to local inflammatory challenge in the CNS and suffered enhanced neuronal degeneration as compared to AcP-deficient or wildtype mice. These findings implicate AcPb as an additional component of the highly regulated IL-1 system and suggest that it may play a role in modulating CNS responses to IL-1 and the interplay between inflam...
BackgroundPD-1/PD-L1 immune checkpoint inhibitors have transformed oncology, but a significant unmet need persists for patients with relapsed/refractory tumors following PD-1/PD-L1 treatment. PD-L1 is expressed in patients across a broad... more
BackgroundPD-1/PD-L1 immune checkpoint inhibitors have transformed oncology, but a significant unmet need persists for patients with relapsed/refractory tumors following PD-1/PD-L1 treatment. PD-L1 is expressed in patients across a broad spectrum of tumor types and displays limited normal tissue expression, highlighting the potential of PD-L1 as a target for antibody-drug conjugates (ADCs) in addition to its role as an immune checkpoint. SGN-PDL1V is a PD-L1-directed ADC currently under preclinical investigation, which is comprised of an anti-PD-L1 antibody conjugated to the vedotin drug-linker. The vedotin drug-linker, consists of the microtubule disrupting agent, monomethyl auristatin E (MMAE), and a protease-cleavable peptide linker, which has been clinically validated in multiple ADC programs including brentuximab vedotin, enfortumab vedotin and polatuzumab vedotin.1–3 The proposed SGN-PDL1V primary mechanism of action is direct cytotoxicity against PD-L1-expressing malignant ce...
Research Interests:
BackgroundTisotumab vedotin (TV) is an investigational antibody-drug conjugate composed of a tissue factor (TF)-directed human monoclonal antibody covalently linked to the microtubule-disrupting agent monomethyl auristatin E (MMAE) via a... more
BackgroundTisotumab vedotin (TV) is an investigational antibody-drug conjugate composed of a tissue factor (TF)-directed human monoclonal antibody covalently linked to the microtubule-disrupting agent monomethyl auristatin E (MMAE) via a protease-cleavable linker. TV demonstrated single agent activity (24% objective response rate [ORR]) in previously treated recurrent or metastatic cervical cancer (NCT03438396) where currently, there is no standard of care and ORRs are typically less than 15% and often of limited duration.1–8 TV is currently being evaluated in combination with pembrolizumab (PD-1 inhibitor), bevacizumab, or carboplatin in cervical cancer (NCT03786081), or as a monotherapy in multiple other solid tumors (NCT03913741, NCT03485209, NCT03657043). The anti-tumor activity of TV may be multimodal as TV can induce tumor cell death through several mechanisms, including direct and bystander MMAE-mediated cytotoxicity, as well as antibody-dependent cellular cytotoxicity (ADCC)...
Research Interests:
Tucatinib is an investigational, oral, small molecule tyrosine kinase inhibitor that is highly selective for the kinase domain of HER2, without significant inhibition of EGFR. Recently, HER2CLIMB (NCT02614794), a pivotal, randomized,... more
Tucatinib is an investigational, oral, small molecule tyrosine kinase inhibitor that is highly selective for the kinase domain of HER2, without significant inhibition of EGFR. Recently, HER2CLIMB (NCT02614794), a pivotal, randomized, international, double-blind trial that evaluated tucatinib or placebo in combination with trastuzumab and capecitabine in patients with HER2+ metastatic breast cancer (MBC) with or without brain metastases, after progression with trastuzumab, pertuzumab, and ado-trastuzumab emtansine (T-DM1), showed superior progression-free and overall survival in patients treated on the tucatinib arm. Adverse events in the tucatinib arm were primarily low grade and occurred at rates similar to what was observed in the placebo arm. In this report, we characterize the in vitro and in vivo activity of tucatinib alone and in combination with T-DM1 in HER2-amplified preclinical models. In vitro assays demonstrate that tucatinib potently suppresses HER2-meditated signaling ...
Research Interests:
Patient-derived xenograft (PDX) models are widely recognized as a powerful preclinical tool. In contrast to cell line-derived xenograft (CDX) models, patient tumors are excised and implanted directly into mice and as such, retain tumor... more
Patient-derived xenograft (PDX) models are widely recognized as a powerful preclinical tool. In contrast to cell line-derived xenograft (CDX) models, patient tumors are excised and implanted directly into mice and as such, retain tumor characteristics that are often lost in cell lines. Multiple studies have shown that PDX models have similar histology, genetic mutations, and gene expression patterns to actual patient samples. Additionally, they reflect diversity of both disease stage and treatment history, enabling an assessment of how these factors may impact therapeutic response to a given treatment. SGN-CD228A, which targets melanotransferrin (CD228, p97, MFI2, MELTF), recently entered Phase I clinical trials. CD228 has broad expression in solid tumors and we are testing SGN-CD228A in a basket trial which includes melanoma, mesothelioma, Her2- breast cancer, pancreatic cancer, colorectal cancer, and non-small cell lung cancer (NSCLC). Within these six indications, CD228 is detect...
Research Interests:
The antibody-drug conjugate enfortumab vedotin (EV; AGS22C3E) targets Nectin-4 expressing tumor cells by delivering MMAE, a potent microtubule disrupting agent, to induce cell death. EV has demonstrated single agent activity and... more
The antibody-drug conjugate enfortumab vedotin (EV; AGS22C3E) targets Nectin-4 expressing tumor cells by delivering MMAE, a potent microtubule disrupting agent, to induce cell death. EV has demonstrated single agent activity and encouraging activity (71% ORR) when combined with pembrolizumab (anti-PD-1) in the 1L setting of cis-ineligible metastatic urothelial carcinoma (mUC) (EV-103, NCT03288545). Here we demonstrated that EV may promote multiple mechanisms of action including bystander cell killing and hallmarks of immunogenic cell death (ICD) including ER stress, immune cell recruitment and activation. Two urothelial carcinoma models, T-24 and UM-UC-3, were engineered to express Nectin-4, and both were sensitive to EV in vitro and in vivo. In these Nectin-4 expressing cell lines, EV internalized with Nectin-4, trafficked to lysosomal vesicles, and released intracellular MMAE as shown by intracellular MMAE accumulation. In addition, EV demonstrated a bystander effect by release of...
Research Interests:
Feline McDonough Sarcoma-like tyrosine kinase 3 (FLT3), a tyrosine-protein kinase involved in hematopoiesis, is detectable on the cell surface of approximately 80% of leukemia isolates from adult patients with acute myeloid leukemia... more
Feline McDonough Sarcoma-like tyrosine kinase 3 (FLT3), a tyrosine-protein kinase involved in hematopoiesis, is detectable on the cell surface of approximately 80% of leukemia isolates from adult patients with acute myeloid leukemia (AML). AMG 553 is an investigational chimeric antigen receptor (CAR) T-cell immunotherapy for the treatment of AML. FLT3 expression analysis and in vitro and in vivo studies were leveraged to evaluate the nonclinical safety of AMG 553. Cynomolgus monkeys administered autologous anti-FLT3 CAR T cells demonstrated no evidence of CAR T-cell-mediated toxicity, expansion, or persistence, likely due to restricted cell surface FLT3 protein expression in healthy animals. This highlights the limited value of such in vivo studies for safety assessment of the CAR T-cell modality when directed against a target with restricted expression. To complement these studies and directly evaluate the potential toxicities of eliciting T-cell-mediated cytotoxicity against cells...
Research Interests:
7032 Background: FMS-like tyrosine kinase 3 (FLT3) is a tyrosine-protein kinase involved in hematopoiesis. In acute myeloid leukemia (AML), higher FLT3 transcript levels, independent of the presence of FLT3 mutations, correlate with... more
7032 Background: FMS-like tyrosine kinase 3 (FLT3) is a tyrosine-protein kinase involved in hematopoiesis. In acute myeloid leukemia (AML), higher FLT3 transcript levels, independent of the presence of FLT3 mutations, correlate with higher leukocyte counts and higher degrees of bone marrow infiltration by leukemic cells. FLT3 protein is detectable on the cell surface of more than 80% of leukemia isolates from adult AML patients whereas FLT3 mutations are present only in approximately one third of patients. AMG 553 is a novel, investigational, adoptive cellular immunotherapy for the treatment of relapsed refractory AML, consisting of autologous T cells genetically modified ex vivo to express a transmembrane chimeric antigen receptor (CAR) to target FLT3 protein on the surface of AML cells irrespective of FLT3 mutational status. Methods: The nonclinical safety evaluation of AMG 553 includes assessment of FLT3 expression in normal tissues; in vitro assessment of cytotoxicity against hu...
Research Interests:
Background To further understand the role of pituitary adenylate cyclase-activating polypeptide 1 (PAC1) receptors in headache disorders, we mapped their expression in tissues of the trigemino-autonomic system by immunohistochemistry and... more
Background To further understand the role of pituitary adenylate cyclase-activating polypeptide 1 (PAC1) receptors in headache disorders, we mapped their expression in tissues of the trigemino-autonomic system by immunohistochemistry and in situ hybridization. Methods To optimize screening for monoclonal antibodies suitable for immunohistochemistry on formalin-fixed, paraffin-embedded tissues, we developed a new enzyme-linked immunosorbent assay using formalin-fixed, paraffin-embedded cells overexpressing human PAC1 receptors. 169G4.1 was selected from these studies for analysis of rat and human tissues and chimerized onto a mouse backbone to avoid human-on-human cross-reactivity. Immunoreactivity was compared to PAC1 receptor mRNA by in situ hybridization in both species. Results 169G4.1 immunoreactivity delineated neuronal cell bodies in the sphenopalatine ganglion in both rat and human, whereas no staining was detected in the trigeminal ganglion. The spinal trigeminal nucleus in ...
Research Interests:
There is an unmet need in severe asthma where approximately 40% of patients exhibit poor beta-agonist responsiveness, suffer daily symptoms and show frequent exacerbations. Antagonists of the calcium-activated chloride channel, TMEM16A,... more
There is an unmet need in severe asthma where approximately 40% of patients exhibit poor beta-agonist responsiveness, suffer daily symptoms and show frequent exacerbations. Antagonists of the calcium-activated chloride channel, TMEM16A, offers a new mechanism to bronchodilate airways and block the multiple contractiles operating in severe disease. To identify TMEM16A antagonists we screened a library of ~580,000 compounds. The anthelmintics niclosamide, nitazoxanide and related compounds were identified as potent TMEM16A antagonists that blocked airway smooth muscle depolarization and contraction. To evaluate whether TMEM16A antagonists resist use- and inflammatory-desensitization pathways limiting beta-agonist action, we tested their efficacy under harsh conditions using maximally contracted airways or airways pretreated with a cytokine cocktail. Stunningly, TMEM16A antagonists fully bronchodilated airways, while the beta-agonist isoproterenol showed only partial effects. Thus, ant...
Research Interests:
Etelcalcetide, a novel peptide agonist of the calcium-sensing receptor, prevents vascular calcification in a rat model of renal insufficiency with secondary hyperparathyroidism. Vascular calcification occurs frequently in patients with... more
Etelcalcetide, a novel peptide agonist of the calcium-sensing receptor, prevents vascular calcification in a rat model of renal insufficiency with secondary hyperparathyroidism. Vascular calcification occurs frequently in patients with chronic kidney disease (CKD) and is a consequence of impaired mineral homeostasis and secondary hyperparathyroidism (SHPT). Etelcalcetide substantially lowers parathyroid hormone (PTH) and fibroblast growth factor-23 (FGF23) levels in SHPT patients on hemodialysis. This study compared the effects of etelcalcetide and paricalcitol on vascular calcification in rats with adenine-induced CKD and SHPT. Uremia and SHPT were induced in male Wistar rats fed a diet supplemented with 0.75% adenine for 4 weeks. Rats were injected with vehicle, etelcalcetide, or paricalcitol for 4 weeks from the beginning of adenine diet. Rats fed an adenine-free diet were included as nonuremic controls. Similar reductions in plasma PTH and parathyroid chief cell proliferation we...
Research Interests: Endocrinology, Biomedical Engineering, Medicine, Internal Medicine, Animals, and 12 moreMale, Peptides, Parathyroid Hormone, Calcified tissue, Clinical Sciences, Rats, Wistar Rats, Hyperparathyroidism, Vascular Calcification, Biochemistry and cell biology, Secondary Hyperparathyroidism, and renal insufficiency
Research Interests:
Sustained elevation of parathyroid hormone (PTH) is catabolic to cortical bone, as evidenced by deterioration in bone structure (cortical porosity), and is a major factor for increased fracture risk in chronic kidney disease (CKD).... more
Sustained elevation of parathyroid hormone (PTH) is catabolic to cortical bone, as evidenced by deterioration in bone structure (cortical porosity), and is a major factor for increased fracture risk in chronic kidney disease (CKD). Etelcalcetide (AMG 416), a novel peptide agonist of the calcium-sensing receptor, reduces PTH levels in subtotal nephrectomized (Nx) rats and in hemodialysis patients with secondary hyperparathyroidism (SHPT) in clinical studies; however, effects of etelcalcetide on bone have not been determined. In a rat model of established SHPT with renal osteodystrophy, etelcalcetide or vehicle was administered by subcutaneous (s.c.) injection to subtotal Nx rats with elevated PTH (>750pg/mL) once per day for 6weeks. Sham-operated rats receiving vehicle (s.c.) served as non-SHPT controls. Prior to treatment, significant increases in serum creatinine (2-fold), blood urea nitrogen (BUN, 3-fold), PTH (5-fold), fibroblast growth factor-23 (FGF23; 13-fold) and osteocalc...
Research Interests: Engineering, Endocrinology, Chemistry, Calcium, Medicine, and 15 moreBiological Sciences, Internal Medicine, Bone, Animals, Male, Osteocalcin, Hyperplasia, Blood Urea Nitrogen, Cortical Bone, Nephrectomy, Creatinine, Biomechanical Phenomena, Medical and Health Sciences, Kidney function tests, and Fibroblast growth factors
The discovery of brown adipose tissue (BAT) as a key regulator of energy expenditure has sparked interest in identifying novel soluble factors capable of activating inducible BAT (iBAT) to combat obesity. Using a high content cell-based... more
The discovery of brown adipose tissue (BAT) as a key regulator of energy expenditure has sparked interest in identifying novel soluble factors capable of activating inducible BAT (iBAT) to combat obesity. Using a high content cell-based screen, we identified Fibroblast Growth Factor (FGF) 16 as a potent inducer of several physical and transcriptional characteristics analogous to those of both classical BAT and iBAT. Over-expression of Fgf16 in vivo recapitulated several of our in vitro findings, specifically significant induction of Ucp1 gene and UCP1 protein expression in inguinal white adipose tissue (iWAT), a common site for emergent active iBAT. Despite significant UCP1 up-regulation in iWAT and dramatic weight loss, the metabolic improvements observed due to Fgf16 over-expression in vivo were not a result of increased energy expenditure, as measured by indirect calorimetric assessment. Instead, a pattern of reduced food and water intake combined with feces replete with lipid an...
Research Interests: Endocrinology, Obesity, Biology, Biological Chemistry, Medicine, and 15 moreSignal Transduction, Biological Sciences, Adipose tissue, Cell line, Humans, Mice, Animals, Fibroblast Growth Factor, CHEMICAL SCIENCES, Brown Adipose Tissue, In Vivo, Receptor, Dietary fats, Medical and Health Sciences, and Fibroblast growth factors
Research Interests:
Research Interests:
Research Interests:
BackgroundSGN-B7H4V is a novel, investigational vedotin antibody drug conjugate (ADC) directed to B7-H4, a member of the B7 family of immune checkpoint ligands. B7-H4 expression is elevated on a variety of solid tumors including breast,... more
BackgroundSGN-B7H4V is a novel, investigational vedotin antibody drug conjugate (ADC) directed to B7-H4, a member of the B7 family of immune checkpoint ligands. B7-H4 expression is elevated on a variety of solid tumors including breast, ovarian, and endometrial tumors.1 SGN-B7H4V is composed of a fully human IgG1 anti-B7-H4 monoclonal antibody (mAb) conjugated to the microtubule disrupting agent monomethyl auristatin E (MMAE) via a protease-cleavable peptide linker. SGN-B7H4V is designed to bind and internalize the immune checkpoint ligand B7-H4/ADC complex from the surface of malignant cells and release the cytotoxic payload MMAE. This ”vedotin” drug linker system has been clinically validated by multiple ADC programs, including brentuximab vedotin, enfortumab vedotin, and polatuzumab vedotin.2–4 Here, we characterize the target antigen B7-H4 and evaluate SGN-B7H4V activity in preclinical models.MethodsB7-H4 expression was characterized by RNA expression and immunohistochemistry ac...