◥ HER2 Po ten cy Tucatinib blocks MAPK and PI3K/AKT signaling through inhibition of HER2 kinase activity
Chemokines play a key role in leukocyte recruitment during inflammation and are implicated in the pathogenesis of a number of autoimmune diseases. As such, inhibiting chemokine signaling has been of keen interest for the development of therapeutic agents. This endeavor, however, has been hampered due to complexities in the chemokine system. Many chemokines have been shown to signal through multiple receptors and, conversely, most chemokine receptors bind to more than one chemokine. One approach to overcoming this complexity is to develop a single therapeutic agent that binds and inactivates multiple chemokines, similar to an immune evasion strategy utilized by a number of viruses. Here, we describe the development and characterization of a novel therapeutic antibody that targets a subset of human CC chemokines, specifically CCL3, CCL4, and CCL5, involved in chronic inflammatory diseases. Using a sequential immunization approach, followed by humanization and phage display affinity maturation, a therapeutic antibody was developed that displays high binding affinity towards the three targeted chemokines. In vitro, this antibody potently inhibits chemotaxis and chemokine-mediated signaling through CCR1 and CCR5, primary chemokine receptors for the targeted chemokines. Furthermore, we have demonstrated in vivo efficacy of the antibody in a SCID-hu mouse model of skin leukocyte migration, thus confirming its potential as a novel therapeutic chemokine antagonist. We anticipate that this antibody will have broad therapeutic utility in the treatment of a number of autoimmune diseases due to its ability to simultaneously neutralize multiple chemokines implicated in disease pathogenesis.
Background: Tucatinib is an orally administered, reversible HER2-targeted small molecule tyrosine kinase inhibitor that potently and selectively inhibits HER2 relative to the closely related kinase EGFR. In a phase Ib clinical trial in HER2+ metastatic breast cancer, tucatinib in combination with the HER2-targeted antibody-drug conjugate (ADC) ado-trastuzumab emtansine (T-DM1) was well tolerated and demonstrated activity in pretreated patients with HER2-positive metastatic breast cancer (Borges VF et al., 2018). Here, we present preclinical data demonstrating tucatinib potentiates the activity of T-DM1 in HER2+ breast cancer models in vitro, and in vivo. In addition, tucatinib also enhanced the activity of a camptothecin-based HER2 ADC comprising trastuzumab conjugated with 8 exatecan moieties (T-Ex). Methods: In vitro assays were conducted to evaluate the potency of tucatinib, T-DM1 and T-Ex as single agents, and in combination, using a panel of breast cancer cell lines expressing various levels of HER2. The combinatorial effects of tucatinib with T-DM1 or T-Ex was assessed by isobologram analysis to determine additivity, synergy or antagonistic properties of the drug combinations. The activity of tucatinib either alone (50 mg/kg BID) or in combination with T-DM1 (10 mg/kg single dose IV) was evaluated in vivo using the HER2+ breast cancer cell line BT-474, and in 3 patient-derived xenograft (PDX) models of HER2+ breast cancer. Results: Tucatinib demonstrated potent anti-tumor activity in HER2 overexpressing cell lines in vitro with a similar selectivity profile as T-DM1 or T-Ex. When co-administered in vitro and subjected to isobologram analysis, tucatinib and T-DM1 or T-Ex combinations produced additive or synergistic effects. Moreover, tucatinib potently inhibited a subset of cell lines that showed reduced sensitivity to either T-DM1 or T-Ex. In BT-474 cells, the co-administration of tucatinib with T-DM1 in vitro was synergistic and resulted in an increased intracellular concentration of the TDM-1 catabolite Lys-MCC-DM1. The combination of tucatinib with T-DM1 was also more effective than either single agent alone in BT-474 xenografts in vivo and increased the number of complete tumor regressions. In 2 of 3 PDX models tested, the combination of tucatinib with T-DM1 was significantly more active than T-DM1 or tucatinib alone and produced a higher proportion of partial or complete tumor regressions compared with the single agent treatments. Conclusions: These data demonstrate tucatinib results in selective and potent anti-tumor activity in HER2+ tumor derived cell lines, including cell lines that show reduced sensitivity to T-DM1 or T-Ex in vitro. The results also demonstrate that tucatinib is either additive or synergistic when combined with T-DM1 or T-Ex in vitro. In addition, tucatinib in combination with T-DM1 showed enhanced anti-tumor activity in vivo in models of HER2+ breast cancer when compared to T-DM1 as a single agent. These results, taken together with the early clinical data demonstrating preliminary safety and activity of tucatinib with T-DM1, support continued assessment of tucatinib in combination with T-DM1, as well as other HER2 targeted ADCs, in HER2+ metastatic breast cancer patients. Borges VF, Ferrario C, Aucoin N, Falkson C, Khan Q, Krop I, Welch S, Conlin A, Chaves J, Bedard PL, Chamberlain M, Gray T, Vo A, Hamilton E. JAMA Oncol. 2018;4(9):1214-1220. Citation Format: Anita Kulukian, Janelle Taylor, Devra Olson, Margo Zaval, Robert Thurman, Shawna Hengel, Lauren Farr, Tim S Lewis, Scott R Peterson. Tucatinib, a HER2-selective tyrosine kinase inhibitor, increases the anti-tumor activity of trastuzumab antibody-drug conjugates in preclinical models of HER2+ breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P1-18-09.
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 pathways, including phosphorylation of HER2, HER3, AKT and ERK. Ex vivo analysis of tucatinib-treated xenografts shows similar suppression of signal transduction pathways. Tucatinib inhibits the proliferation of HER2+ breast cancer (BC) cell lines in vitro with single digit nanomolar potencies, but was inactive in blocking cell proliferation of BC cell lines lacking amplified HER2. In HER2-amplified BC cell line derived- and patient-derived xenograft models, tucatinib suppresses growth of tumors as a single agent and shows improved activity when combined with T-DM1. To evaluate activity and drug penetration in HER2+ metastatic CNS tumors, we developed and characterized a red-shifted luciferase-expressing BT-474 BC cell line which was stereotaxically implanted into the brain. In vivo bioluminescence imaging was used to evaluate the efficacy of tucatinib and T-DM1 in CNS tumors as single agents and in combination. Histological assessment of treated tumors suggests that tucatinib can penetrate the blood-brain tumor barrier to suppress HER2 signaling. These data are further supported by a drug penetration study of CNS-implanted BT-474 tumors. Quantitative autoradiography analysis demonstrates that 14C-labeled tucatinib penetrates the CNS tumor mass with drug concentration levels exceeding measurements in normal brain regions. These data demonstrate that tucatinib is a uniquely selective and highly potent inhibitor of HER2 signaling, with activity against HER2+ breast cancer xenograft and brain metastasis models. Tucatinib is effective against implanted CNS tumors, suggesting that therapeutically relevant drug concentrations are achievable. These preclinical findings are consistent with clinical data showing tucatinib activity in patients with HER2+ MBC with brain metastases and support the continued development of tucatinib in patients with HER2+ BC. Citation Format: Devra J. Olson, Anita Kulukian, Janelle D. Taylor, Margo C. Zaval, Albina Nesterova, Kelly M. Hensley, Michelle L. Ulrich, Nicole S. Stevens, Scott R. Peterson. Preclinical characterization of tucatinib in HER2-amplified xenograft and CNS implanted tumors [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1962.
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