HER2 Support Group Forums - View Single Post - new article by Genentech authors--herceptin TM1 works equivanlently2 herceptin AND

Lani · 09-12-2010, 07:31 AM

active vs. lapatinib resistant tumors

ie, adding on the strong "poison", the maytansine derivative, to the herceptin did not change its pharmacokinetics (how long it lasts, how it is distributed, etc) nor how it worked ie, same as herceptin without the addition of the maytansine derivative, but it also worked against those tumor cell lines which had developed resistance to lapatinib

Interesting conclusion and discussion of future hopes--see info at end

Breast Cancer Res Treat. 2010 Aug 21. [Epub ahead of print]
Trastuzumab-DM1 (T-DM1) retains all the mechanisms of action of trastuzumab and efficiently inhibits growth of lapatinib insensitive breast cancer.
Junttila TT, Li G, Parsons K, Phillips GL, Sliwkowski MX.

Research Oncology, Genentech, Inc., 1 DNA Way, Mailstop 72, South San Francisco, CA, 94080, USA.
Abstract
Trastuzumab (Herceptin((R))) is currently used as a treatment for patients whose breast tumors overexpress HER2/ErbB2. Trastuzumab-DM1 (T-DM1, trastuzumab emtansine) is designed to combine the clinical benefits of trastuzumab with a potent microtubule-disrupting drug, DM1 (a maytansine derivative). Currently T-DM1 is being tested in multiple clinical trials. The mechanisms of action for trastuzumab include inhibition of PI3K/AKT signaling pathway, inhibition of HER-2 shedding and Fcgamma receptor mediated engagement of immune cells, which may result in antibody-dependent cellular cytotoxicity (ADCC). Here we report that T-DM1 retains the mechanisms of action of unconjugated trastuzumab and is active against lapatinib resistant cell lines and tumors.

PMID: 20730488

In the present report, we address whether chemical modification of trastuzumab affects its known mechanisms of action. The anti-signaling properties of trastuzumab are primarily the consequence of antibody recognition of HER2 on the surface of breast cancer cells. Our studies confirm that T-DM1 binding to HER2 is not affected by the derivatization with MCC-DM1. As expected, once bound to HER2, T-DM1 blocks HER2 shedding. Perhaps more importantly, T-DM1 also downregulates PI3K-AKT signaling due to the fact that, like trastuzumab [11], it effectively disrupts the constitutive HER2–HER3 complex. Activation of immune effector function requires binding of the antibody’s Fc region to Fcγ receptors. Antibody-dependent cytotoxicity assays (ADCC) performed with peripheral blood mononuclear cells obtained from health volunteers verified that T-DM1 maintains full trastuzumab activity.

Most novel anticancer agents are initially tested in model systems that are refractory to standard of care therapies. To date our preclinical focus with T-DM1 has examined tumor models that are refractory to trastuzumab. Our clinical studies have also selected patients whose tumors have progressed through Herceptin® and in many cases Tykerb® (lapatinib). In the current report we demonstrate that T-DM1 efficiently inhibits growth of cells and tumors that are insensitive to lapatinib and have hyperactivated PI3K signaling due to activating mutations in p110α. Because the T-DM1 preclinical and clinical data are promising, we are now designing and executing clinical trials that will examine T-DM1’s activity in patients who may not have received previous HER2 directed therapies. The data presented in this report suggest that T-DM1 maintains all of the known mechanisms of action of trastuzumab. As a result of these findings, we are optimistic that T-DM1 can be moved into earlier lines of therapy for the treatment of HER2 positive cancer.

Conflict of interest
All authors are employees of Genentech, Inc.

09-12-2010, 07:31 AM	#1
Lani Senior Member Join Date: Mar 2006 Posts: 4,778	new article by Genentech authors--herceptin TM1 works equivanlently2 herceptin AND active vs. lapatinib resistant tumors ie, adding on the strong "poison", the maytansine derivative, to the herceptin did not change its pharmacokinetics (how long it lasts, how it is distributed, etc) nor how it worked ie, same as herceptin without the addition of the maytansine derivative, but it also worked against those tumor cell lines which had developed resistance to lapatinib Interesting conclusion and discussion of future hopes--see info at end Breast Cancer Res Treat. 2010 Aug 21. [Epub ahead of print] Trastuzumab-DM1 (T-DM1) retains all the mechanisms of action of trastuzumab and efficiently inhibits growth of lapatinib insensitive breast cancer. Junttila TT, Li G, Parsons K, Phillips GL, Sliwkowski MX. Research Oncology, Genentech, Inc., 1 DNA Way, Mailstop 72, South San Francisco, CA, 94080, USA. Abstract Trastuzumab (Herceptin((R))) is currently used as a treatment for patients whose breast tumors overexpress HER2/ErbB2. Trastuzumab-DM1 (T-DM1, trastuzumab emtansine) is designed to combine the clinical benefits of trastuzumab with a potent microtubule-disrupting drug, DM1 (a maytansine derivative). Currently T-DM1 is being tested in multiple clinical trials. The mechanisms of action for trastuzumab include inhibition of PI3K/AKT signaling pathway, inhibition of HER-2 shedding and Fcgamma receptor mediated engagement of immune cells, which may result in antibody-dependent cellular cytotoxicity (ADCC). Here we report that T-DM1 retains the mechanisms of action of unconjugated trastuzumab and is active against lapatinib resistant cell lines and tumors. PMID: 20730488 In the present report, we address whether chemical modification of trastuzumab affects its known mechanisms of action. The anti-signaling properties of trastuzumab are primarily the consequence of antibody recognition of HER2 on the surface of breast cancer cells. Our studies confirm that T-DM1 binding to HER2 is not affected by the derivatization with MCC-DM1. As expected, once bound to HER2, T-DM1 blocks HER2 shedding. Perhaps more importantly, T-DM1 also downregulates PI3K-AKT signaling due to the fact that, like trastuzumab [11], it effectively disrupts the constitutive HER2–HER3 complex. Activation of immune effector function requires binding of the antibody’s Fc region to Fcγ receptors. Antibody-dependent cytotoxicity assays (ADCC) performed with peripheral blood mononuclear cells obtained from health volunteers verified that T-DM1 maintains full trastuzumab activity. Most novel anticancer agents are initially tested in model systems that are refractory to standard of care therapies. To date our preclinical focus with T-DM1 has examined tumor models that are refractory to trastuzumab. Our clinical studies have also selected patients whose tumors have progressed through Herceptin® and in many cases Tykerb® (lapatinib). In the current report we demonstrate that T-DM1 efficiently inhibits growth of cells and tumors that are insensitive to lapatinib and have hyperactivated PI3K signaling due to activating mutations in p110α. Because the T-DM1 preclinical and clinical data are promising, we are now designing and executing clinical trials that will examine T-DM1’s activity in patients who may not have received previous HER2 directed therapies. The data presented in this report suggest that T-DM1 maintains all of the known mechanisms of action of trastuzumab. As a result of these findings, we are optimistic that T-DM1 can be moved into earlier lines of therapy for the treatment of HER2 positive cancer. Conflict of interest All authors are employees of Genentech, Inc.