Entity

Time filter

Source Type

New Haven, CT, United States

Alvarado D.,University of Pennsylvania | Alvarado D.,Kolltan Pharmaceuticals | Klein D.E.,University of Pennsylvania | Klein D.E.,Harvard University | Lemmon M.A.,University of Pennsylvania
Cell | Year: 2010

Transmwembrane signaling by the epidermal growth factor receptor (EGFR) involves ligand-induced dimerization and allosteric regulation of the intracellular tyrosine kinase domain. Crystallographic studies have shown how ligand binding induces dimerization of the EGFR extracellular region but cannot explain the "high-affinity" and "low-affinity" classes of cell-surface EGF-binding sites inferred from curved Scatchard plots. From a series of crystal structures of the Drosophila EGFR extracellular region, we show here how Scatchard plot curvature arises from negatively cooperative ligand binding. The first ligand-binding event induces formation of an asymmetric dimer with only one bound ligand. The unoccupied site in this dimer is structurally restrained, leading to reduced affinity for binding of the second ligand, and thus negative cooperativity. Our results explain the cell-surface binding characteristics of EGF receptors and suggest how individual EGFR ligands might stabilize distinct dimeric species with different signaling properties. PaperFlick: © 2010 Elsevier Inc. Source


Patent
Kolltan Pharmaceuticals | Date: 2012-01-25

Provided herein, in one aspect, are antibodies that immunospecifically bind to a human KIT antigen comprising the fourth and/or fifth extracellular Ig-like domains (that is, D4 and/or D5 domains), polynucleotides comprising nucleotide sequences encoding such antibodies, and expression vectors and host cells for producing such antibodies. The antibodies can inhibit KIT activity, such as ligand-induced receptor phosphorylation. Also provided herein are kits and pharmaceutical compositions comprising antibodies that specifically bind to a KIT antigen, as well as methods of treating or managing a KIT-mediated disorder or disease and methods of diagnosing a KIT-mediated disorder or disease using the antibodies described herein.


Patent
Kolltan Pharmaceuticals | Date: 2013-07-24

Provided herein, in one aspect, are antibodies that immunospecifically bind to a human KIT antigen comprising the fourth and/or fifth extracellular Ig-like domains (that is, D4 and/or D5 domains), polynucleotides comprising nucleotide sequences encoding such antibodies, and expression vectors and host cells for producing such antibodies. The antibodies can inhibit KIT activity, such as ligand-induced receptor phosphorylation. Also provided herein are kits and pharmaceutical compositions comprising antibodies that specifically bind to a KIT antigen, as well as methods of treating or managing a KIT-associated disorder or disease and methods of diagnosing a KIT-associated disorder or disease using the antibodies described herein.


NEW HAVEN, Conn.--(BUSINESS WIRE)--Kolltan Pharmaceuticals, Inc., a privately held clinical-stage company focused on the discovery and development of novel antibody-based drugs targeting receptor tyrosine kinases, today announced key oral and poster presentations related to its lead development programs at upcoming conferences. An abstract on the Company’s anti-KIT monoclonal antibody drug candidate, KTN0158, has been chosen for oral presentation at the 30th Annual Society for Immunotherapy of Cancer (SITC) Conference, being held November 4- 8 in National Harbor, Maryland. Kolltan will also be presenting preclinical data on KTN0158 and KTN3379, its anti-ErbB3 monoclonal antibody drug candidate, at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics, being held November 5- 9 in Boston, Massachusetts. Kolltan will be presenting data from a preclinical study evaluating the targeting of KIT on innate immune cells that enhances the antitumor activity of checkpoint inhibitors in vivo. KTN0158 is a proprietary, humanized anti-KIT IgG1 monoclonal antibody drug candidate being developed as a potential antibody-based therapy for cancer and mast cell-related diseases. The Company plans to file an investigational new drug application (IND) for KTN0158 with the FDA in the fourth quarter of 2015. Targeting KIT on Innate Immune Cells enhances the Antitumor Activity of Checkpoint Inhibitors in vivo (Abstract ID 112276) Authors: Richard Gedrich, Scott Seibel, and Theresa LaVallee, Translational Medicine, Kolltan Pharmaceuticals, Inc., New Haven, CT; Joseph Paul Eder, Yale Cancer Center, New Haven, CT Kolltan also will present data on KTN0158 from a preclinical study evaluating KTN0158 in dogs with spontaneous mast cell tumors. Authors: Cheryl London, Sarah Rippy, Heather Gardner, Gerald Post, Neal Janson, Linda Crew, Theresa LaVallee, and Richard Gedrich, The Ohio State University, Columbus, OH, The Veterinary Cancer Center, Norwalk CT, and Kolltan Pharmaceuticals, Inc., New Haven, CT Speaker: Cheryl London, DVM, PhD, Diplomate ACVIM (Oncology), Professor, The Thekla R. and Donald B. Shackelford Professorship in Canine Medicine, The Ohio State University An additional poster at EORTC will feature preclinical data for Kolltan’s anti-ErbB3 (HER3) monoclonal antibody drug candidate, KTN3379. The Company will be presenting preclinical data that supports potential Phase 2 studies in BRAF mutant cancers and other tumor settings. Authors: Gwenda F. Ligon, Jay S. Lillquist, Edward J. Natoli, Jr., Jennifer A. Pendleton, Ada Y. Vail, Andrew R. Proffitt, Christine Y Lubeski, J. Paul Eder, Carolyn F. Sidor, Ronald A. Peck, Theresa M. LaVallee, and Diego Alvarado, Kolltan Pharmaceuticals, Inc., New Haven, CT; Yale Cancer Center, New Haven, CT KTN3379 is a human monoclonal antibody designed to block the activity of ErbB3 (HER3), a receptor tyrosine kinase (RTK) that belongs to the epidermal growth factor receptor, or EGFR, family. ErbB3 is believed to be an important receptor regulating cancer cell growth and survival. ErbB3 is expressed in many cancers, including head and neck, breast, lung, gastric, and melanoma. While there are several successful currently marketed products targeting two members of the EGFR family, there are none that directly target ErbB3. In cancer, ErbB3 activation can be driven by its ligand, neuregulin (NRG), or in its absence, through overexpression of its co-receptor ErbB2 (HER2). Kolltan is conducting multiple clinical trials evaluating KTN3379 in the treatment of solid tumors. These trials include an ongoing Phase 1b multi-center, open-label, dose escalation clinical trial of KTN3379 in patients with solid tumors, with expansion cohorts testing KTN3379 in combination with cetuximab, erlotinib, vemurafenib, or trastuzumab. In addition, the Company is conducting a Phase 1b study in thyroid cancer, evaluating the treatment of patients with radioactive iodine refractory BRAF mutated cancers with a combination of KTN3379 and vemurafenib. A third clinical study is evaluating tissue responses to KTN3379 in newly diagnosed patients with head and neck cancers who are treated with KTN3379 prior to their surgical resection. KTN0158 is a proprietary, humanized monoclonal antibody designed using structure-based approaches to block the activation of KIT, an RTK that is expressed on many cancers and mast cells. Kolltan applied novel insights about the x-ray crystallographic structure of the KIT receptor to identify a unique way to inhibit the function of KIT through binding to the domain that is near the cell membrane and blocking dimerization. This targeting of KIT proximal to the membrane is a novel approach compared to targeting the ligand and led to Kolltan’s discovery of KTN0158. There are currently no KIT-targeting antibodies on the market for any disease indication. In oncology, KIT is expressed in tumors such as GIST, melanoma, AML, SCLC, and others. No KIT-targeting drugs are approved for non-GIST tumor types and treatment of GIST tumors with approved multi-targeted small-molecule tyrosine kinase inhibitors (TKIs) does not always lead to long-term clinical benefit due to resistance, including secondary mutations that overcome small-molecule drug approaches. As a monoclonal antibody, the Company believes KTN0158 is particularly suited to block KIT dimerization and inhibit activation and signaling of the receptor and therefore lead to potent inhibition of both wild-type and mutant KIT forms. Kolltan is planning to file an IND with the FDA for KTN0158 in 2015 followed by the initiation of clinical trials in oncology in 2016. A second IND filing for KTN0158 is anticipated in 2016 for neurofibromatosis 1 (NF1). KIT and mast cells have been associated with the etiology of NF1, an orphan disease afflicting approximately 100,000 individuals in the U.S. Kolltan, a privately held clinical-stage company, is focused on the discovery and development of novel, antibody-based drugs targeting RTKs for the treatment of cancer and other diseases with significant unmet need. Kolltan’s founders and members of its management team have deep expertise and a proven track record in drug discovery, development, and commercialization of innovative therapeutics, including drugs targeting RTKs. Kolltan is working in close collaboration with the laboratory of Kolltan Co-Founder, Dr. Joseph Schlessinger, as well as the Yale University medical and scientific community. The Company has a broad and novel portfolio of therapeutic biologics targeting multiple RTKs that are advancing in clinical and preclinical development and are expected to generate multiple near-term milestones. Kolltan’s most advanced product candidates include KTN3379, a human monoclonal antibody designed to block the activity of ErbB3 which is in Phase 1b clinical trials in solid tumors, and KTN0158, a humanized monoclonal antibody designed to block the activation of KIT, which is being developed as a potential therapy for cancer and mast cell-related diseases and is anticipated to enter clinical trials in early 2016. Any statements in this news release about future expectations, plans and prospects for Kolltan constitute forward-looking statements. Actual results may differ materially from those indicated by such forward-looking statements as a result of a variety of important factors. Kolltan anticipates that subsequent events and developments may cause its views to change. However, while Kolltan may elect to update these forward-looking statements in the future, Kolltan specifically disclaims any obligation to do so.


NEW HAVEN, Conn.--(BUSINESS WIRE)--Kolltan Pharmaceuticals, Inc. today announced the presentation of interim results from an ongoing Phase 1b study of KTN3379, a human anti-ErbB3 (HER3) monoclonal antibody drug candidate being developed for the treatment of adult patients with advanced solid tumors. The interim results established a recommended Phase 2 dose of KTN3379, demonstrated good tolerability, and showed early signs of activity in combination with other targeted agents. The results were presented in a poster titled “A Phase 1, Open-label Study to Evaluate the Safety and Pharmacokinetics of the Anti-ErbB3 Antibody, KTN3379, Alone or in Combination with Targeted Therapies in Patients with Advanced Tumors” (Abstract #2598, Developmental Therapeutics—Clinical Pharmacology and Experimental Therapeutics Sat, May 30, 8:00 AM - 11:30 AM CDT, Location: S Hall at the 2015 American Society of Clinical Oncology Annual Meeting in Chicago). “Targeting ErbB3 for the treatment of multiple types of cancers is an important strategy as ErbB3 participates in tumor survival pathways and may serve as a resistance mechanism for widely-used therapies including agents against other ErbB family members such as HER2 and EGFR,” stated Dr. Todd Bauer of the Sarah Cannon Research Institute in Nashville, TN. “The results for this first-in-human study of KTN3379 demonstrate an acceptable safety profile for further clinical development of the drug candidate and pharmacokinetics consistent with dosing once every three weeks. These data also provide a rationale for Phase 2 investigation of KTN3379 as a novel anti-cancer therapy in combination with other targeted agents.” “We are delighted with the clinical progress of KTN3379 in that we were able to move quickly from the single agent dose escalation cohorts into combinations based on the safety profile and favorable pharmacokinetic properties shown in this study,” said Dr. Carolyn Sidor, Chief Medical Officer at Kolltan. “The results allow us to plan multiple Phase 2 studies of KTN3379 based on its pharmacokinetics and potentially favorable dosing schedule and what we believe to be its novel binding and dual mechanism of action. Plans are underway to conduct Phase 2 studies in therapeutic combinations in selected solid tumors along with additional Phase 1 studies in head and neck cancer and thyroid cancer beginning this year.” The ongoing Phase 1b study is a multi-center, open-label, dose escalation study, in which KTN3379 was administered at doses of 5, 10, 15, or 20 mg/kg, or a fixed dose of 1,200 mg, once every three weeks as one hour IV infusions. This was followed by expansion cohorts of six to twelve patients each using 20 mg/kg of KTN3379 in combination with cetuximab, erlotinib, vemurafenib, or trastuzumab. Pharmacokinetic profiling, anti-drug antibodies, pharmacodynamic, and other biomarker analyses were performed. The ASCO presentation includes the following interim results and data: KTN3379 is a human monoclonal antibody designed to block the activity of ErbB3 (HER3), an RTK that belongs to the epidermal growth factor receptor, or EGFR, family. ErbB3 is believed to be an important receptor regulating cancer cell growth and survival. ErbB3 is expressed in many cancers including head and neck, breast, lung, gastric and melanoma. While there are several successful currently marketed products targeting two members of the EGFR family, there are none that directly target ErbB3. In cancer, ErbB3 activation can be driven by its ligand, neuregulin (NRG), or in its absence, through overexpression of its co-receptor ErbB2 (HER2). Kolltan, a privately held clinical-stage company, is focused on the discovery and development of novel antibody-based drugs targeting receptor tyrosine kinases for the treatment of cancer and other diseases with significant unmet need. Kolltan’s founders and members of its management team have deep expertise and a proven track record in drug discovery, development and commercialization of innovative therapeutics, including drugs targeting kinases. Kolltan is working in close collaboration with the laboratory of Kolltan Co-Founder, Dr. Joseph Schlessinger, as well as the Yale University medical and scientific community. The Company has a broad and novel portfolio of therapeutic biologics targeting multiple receptor tyrosine kinases that are advancing in clinical and preclinical development and are expected to generate multiple near-term milestones.

Discover hidden collaborations