Phase 1 Data Supports Evaluating Combinations with Targeted Therapies in Ongoing Phase 1B
NEW HAVEN, CT, USA I November 20, 2014 I Kolltan Pharmaceuticals, Inc. today presented clinical data from a Phase 1 clinical trial of KTN3379 and preclinical crystallographic structure data supporting a novel epitope and mechanism of action at the 26th EORTC-NCI-AACR Symposium on Molecular Targets andCancer Therapeutics in Barcelona, Spain. Kolltan is a privately held biopharmaceutical company focused on the discovery and development of novel antibody-based drugs targeting receptor tyrosine kinases (RTKs).
The Phase 1 clinical trial evaluated KTN3379 to determine initial safety and pharmacokinetics and a recommended Phase 2 dose and schedule. Results from the study were presented by Dr. Pat LoRusso of the Karmanos Research Institute (now at Yale University) and included the following findings:
- KTN3379 administered at doses of 5, 10 and 20mg/kg every 21 days was well tolerated with no dose limiting toxicities; a maximum tolerated dose was not determined.
- Pharmacokinetic parameters for KTN3379 were linear and dose proportional based on the concentration of antibody in the patients’ blood.
- Levels of KTN3379 in patients’ blood at doses of 10 and 20 mg/kg exceeded the target exposure determined from experiments assessing antitumor activity in preclinical models.
- Modulation of soluble ErbB3, a biomarker circulating in the patients’ blood, was observed in response to KTN3379 treatment at all doses tested, demonstrating a change in response to antibody treatment.
In a separate presentation, Kolltan presented data from preclinical experiments in which KTN3379 inhibited both ligand dependent and ErbB2 dependent (ligand independent) ErbB3 activation in different tumor types. The crystallographic structure of the KTN3379 antigen-binding fragment (Fab) was determined in complex with the complete ErbB3 extracellular domain. The structure of the complex revealed that the antibody binds with very high affinity to a novel epitope in the boundary between domains 2 and 3 and locks ErbB3 in its inactive state. In collaboration between Kolltan and Joseph Schlessinger, Ph.D., Chair of the Department of Pharmacology, Director of the Cancer Biology Institute at Yale University and Kolltan Co-Founder, the authors concluded that KTN3379 inhibits ErbB3 in the first step of its activation and prevents both neuregulin binding and receptor heterodimerization activation. In summary the data revealed that:
- KTN3379 binds ErbB3 with high affinity, which contributes to its ability to inhibit ErbB3 over time. The antibody binds to a unique epitope in ErbB3 domains 2 and 3 and holds ErbB3 in an inactive conformation that is unable to bind neuregulin or dimerize with other receptors.
- Generally, the heavy chain of an antibody binds its target. In this study, the data demonstrate that the KTN3379 light chain mediates interactions with the hinge region of ErbB3,locking the receptor in its auto-inhibited state and contributing to its potency.
- This mechanism for inhibiting ErbB3 activation is distinct from other antibodies that block activation by neuregulin by directly competing for the same binding site.
- This mechanism for inhibiting ErbB3 may also be an approach for EGFR and ErbB4. Conservation of the overall KTN3379 epitope architecture in EGFR and ErbB4 suggests novel ways to develop potent therapeutic antibodies against these targets in addition to ErbB3.
“The data presented are an important step in the development of KTN3379. We now have single agent data showing appropriate pharmacokinetic properties and no evidence of significant toxicity and which support a unique mechanism of action,” said Jerry McMahon, Ph.D., President and Chief Executive Officer of Kolltan Pharmaceuticals. “The crystallographic structure elucidated the mechanism where KTN3379 binds to a unique epitope preventing ErbB3 signaling driven by neuregulin or ErbB2 over expression. These data support our initiation of the ongoing Phase 1B study to evaluate KTN3379 in combination with each of four targeted therapies approved for lung, colorectal, breast, melanoma and head and neck cancers.”
About KTN3379
KTN3379 is a human monoclonal antibody designed to block the activity of ErbB3, 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, colorectal, lung, gastric, ovarian and melanoma. While there are several successful currently marketed products targeting two members of the EGFR family, there are none that directly target ErbB3. ErbB3 signaling plays an important role in the progression of several solid tumor types, and is the target of several therapeutic monoclonal antibodies. In cancer, ErbB3 activation can be driven by its ligand, neuregulin, or in its absence, through overexpression of its co-receptor ErbB2.
About Kolltan Pharmaceuticals
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. Located adjacent to the Yale Medical School in New Haven, Connecticut, Kolltan is working in close collaboration with the laboratory of Kolltan Co-Founder, Dr. Joseph Schlessinger, as well as the Yale medical and scientific community to bring important medicines to cancer patients and other patients with serious diseases. In addition to KTN3379, the company has two preclinical programs targeting the KIT RTK for inflammatory diseases and oncology as well as a discovery pipeline consisting of product candidates directed at a range of RTK targets.
SOURCE: Kolltan Pharmaceuticals
Post Views: 122
Phase 1 Data Supports Evaluating Combinations with Targeted Therapies in Ongoing Phase 1B
NEW HAVEN, CT, USA I November 20, 2014 I Kolltan Pharmaceuticals, Inc. today presented clinical data from a Phase 1 clinical trial of KTN3379 and preclinical crystallographic structure data supporting a novel epitope and mechanism of action at the 26th EORTC-NCI-AACR Symposium on Molecular Targets andCancer Therapeutics in Barcelona, Spain. Kolltan is a privately held biopharmaceutical company focused on the discovery and development of novel antibody-based drugs targeting receptor tyrosine kinases (RTKs).
The Phase 1 clinical trial evaluated KTN3379 to determine initial safety and pharmacokinetics and a recommended Phase 2 dose and schedule. Results from the study were presented by Dr. Pat LoRusso of the Karmanos Research Institute (now at Yale University) and included the following findings:
- KTN3379 administered at doses of 5, 10 and 20mg/kg every 21 days was well tolerated with no dose limiting toxicities; a maximum tolerated dose was not determined.
- Pharmacokinetic parameters for KTN3379 were linear and dose proportional based on the concentration of antibody in the patients’ blood.
- Levels of KTN3379 in patients’ blood at doses of 10 and 20 mg/kg exceeded the target exposure determined from experiments assessing antitumor activity in preclinical models.
- Modulation of soluble ErbB3, a biomarker circulating in the patients’ blood, was observed in response to KTN3379 treatment at all doses tested, demonstrating a change in response to antibody treatment.
In a separate presentation, Kolltan presented data from preclinical experiments in which KTN3379 inhibited both ligand dependent and ErbB2 dependent (ligand independent) ErbB3 activation in different tumor types. The crystallographic structure of the KTN3379 antigen-binding fragment (Fab) was determined in complex with the complete ErbB3 extracellular domain. The structure of the complex revealed that the antibody binds with very high affinity to a novel epitope in the boundary between domains 2 and 3 and locks ErbB3 in its inactive state. In collaboration between Kolltan and Joseph Schlessinger, Ph.D., Chair of the Department of Pharmacology, Director of the Cancer Biology Institute at Yale University and Kolltan Co-Founder, the authors concluded that KTN3379 inhibits ErbB3 in the first step of its activation and prevents both neuregulin binding and receptor heterodimerization activation. In summary the data revealed that:
- KTN3379 binds ErbB3 with high affinity, which contributes to its ability to inhibit ErbB3 over time. The antibody binds to a unique epitope in ErbB3 domains 2 and 3 and holds ErbB3 in an inactive conformation that is unable to bind neuregulin or dimerize with other receptors.
- Generally, the heavy chain of an antibody binds its target. In this study, the data demonstrate that the KTN3379 light chain mediates interactions with the hinge region of ErbB3,locking the receptor in its auto-inhibited state and contributing to its potency.
- This mechanism for inhibiting ErbB3 activation is distinct from other antibodies that block activation by neuregulin by directly competing for the same binding site.
- This mechanism for inhibiting ErbB3 may also be an approach for EGFR and ErbB4. Conservation of the overall KTN3379 epitope architecture in EGFR and ErbB4 suggests novel ways to develop potent therapeutic antibodies against these targets in addition to ErbB3.
“The data presented are an important step in the development of KTN3379. We now have single agent data showing appropriate pharmacokinetic properties and no evidence of significant toxicity and which support a unique mechanism of action,” said Jerry McMahon, Ph.D., President and Chief Executive Officer of Kolltan Pharmaceuticals. “The crystallographic structure elucidated the mechanism where KTN3379 binds to a unique epitope preventing ErbB3 signaling driven by neuregulin or ErbB2 over expression. These data support our initiation of the ongoing Phase 1B study to evaluate KTN3379 in combination with each of four targeted therapies approved for lung, colorectal, breast, melanoma and head and neck cancers.”
About KTN3379
KTN3379 is a human monoclonal antibody designed to block the activity of ErbB3, 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, colorectal, lung, gastric, ovarian and melanoma. While there are several successful currently marketed products targeting two members of the EGFR family, there are none that directly target ErbB3. ErbB3 signaling plays an important role in the progression of several solid tumor types, and is the target of several therapeutic monoclonal antibodies. In cancer, ErbB3 activation can be driven by its ligand, neuregulin, or in its absence, through overexpression of its co-receptor ErbB2.
About Kolltan Pharmaceuticals
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. Located adjacent to the Yale Medical School in New Haven, Connecticut, Kolltan is working in close collaboration with the laboratory of Kolltan Co-Founder, Dr. Joseph Schlessinger, as well as the Yale medical and scientific community to bring important medicines to cancer patients and other patients with serious diseases. In addition to KTN3379, the company has two preclinical programs targeting the KIT RTK for inflammatory diseases and oncology as well as a discovery pipeline consisting of product candidates directed at a range of RTK targets.
SOURCE: Kolltan Pharmaceuticals
Post Views: 122
