【SABCS2015】双互补位H...
[PD5-08] A biparatopic HER2-targeting antibody-drug conjugate demonstrates potent antitumor activity in primary tumor models that are refractory to or ineligible for HER2-targeted therapies.
Li JY, Perry SR, Muniz-Medina V, Wetzel LK, Rebelatto MC, Bezabeh BZ, Fleming RL, Dimasi N, Gao C, Wu H, Jenkins DW, Osbourn JK, Coats SR.
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MedImmune LLC, Gaithersburg, MD; MedImmune Ltd, Cambridge, United Kingdom.
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lulzcCurrent HER2-targeted drugs are ineffective in killing cancer cells expressing relatively low levels of HER2. Therefore, more than 60% of breast cancer patients are ineligible for HER2-targeted therapies becau of lack of HER2 overexpression and the vast majority of eligible patients who initially respond to the treatment will eventually relap. MedImmune is developing a novel HER2-targeting antibody-drug conjugate (ADC) to address this unmet medical need. We show that a bivalent biparatopic antibody targeting two distinct non-overlaff吧
美国俚语网>escort形近字apping epitopes on HER2 is able to induce receptor clustering on the tumor cell surface, which in turn facilitates internalization and promotes lysosomal trafficking and degradation. When conjugated with a tubulysin-bad microtubule inhibitor, the biparatopic antibody can deliver a greater quantity of cytotoxin into the targeted cancer cells. As a result, it demonstrated superior antitumor activity over Kadcyla (T-DM1) in HER2-overexpressing (HER2-positive) tumor models. It also induced complete tumor regression in a HER2-positive tumor model that had developed acquired resistance to T-DM1 through chronic exposure. Moreover, to explore the potential clinical applications in treating the HER2 non-overexpressing (HER2-negative) patients the biparatopic ADC was evaluated across 17 primary tumor models derived from HER2-negative breast cancer patients among which 13 were triple-negative. Other criteria were also considered in the lection of the 17 models, including the degree of heterogeneity in HER2 expression, ER/PR status and histopathologic subclass, to maximize the diversity of tumor subtypes in the study. The biparatopic ADC demonstrated potent antitumor activity regardless of the histopathologic subclass and ER/PR status of the tumor. At the do of cloudera
1 mg/kg, 41% of the tumor models (7 out of 17) showed tumor regression and 6% (1 out of 17) showed tumor stasis. At the do of 3 mg/kg, 71% of the models (12 out of 17) showed tumor regression and 12% (2 out of 17) showed tumor stasis. Overall, our findings underscore the potential u of this novel HER2-targeting ADC to treat a large patient population that is ineligible for or relapd/refractory to current HER2-targeted therapies, and thus warrant investigation in the clinic.
我最喜欢的一首诗Thursday, December 10, 2015 5:00 PM
Poster Discussion: Her2 (5:00 PM-7:00 PM)
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