Combination therapies comprising anti-ERBB3 agents
Inventors
Zhang, Bo • McDonagh, Charlotte • Huhalov, Alexandra
Assignees
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Publication Number
US-9345766-B2
Publication Date
2016-05-24
Expiration Date
Abstract
Disclosed are methods and compositions for inhibiting the growth of a tumor (e.g., a malignant tumor) in a subject. In particular, combination therapies for treating a tumor in a subject by co-administering an agent selected from i) an effective amount of an anti-estrogen agent; ii) an effective amount of a receptor tyrosine kinase inhibitor; iii) an effective amount of a MEK/PI3 kinase/AKT inhibitor; iv) an effective amount of MM-151; v) an effective amount of an mTOR inhibitor; and/or vi) an effective amount of trastuzumab or TMD1, and/or combinations thereof; and an effective amount of a bispecific anti-ErbB2/anti-ErbB3 antibody. Also disclosed is a bispecific anti-ErbB2/anti-ErbB3 antibody for use in the therapy of a tumor in combination with an agent selected from i) an effective amount of an anti-estrogen agent; ii) an effective amount of a receptor tyrosine kinase inhibitor; iii) an effective amount of a MEK/PI3 kinase/AKT inhibitor; iv) an effective amount of MM-151; v) an effective amount of an mTOR inhibitor; and/or vi) an effective amount of trastuzumab or TMD1, and/or combinations thereof.
Core Innovation
The invention relates to a method of treating a subject with a malignant tumor by co-administering an effective amount of trametinib and a bispecific anti-ErbB2/anti-ErbB3 antibody. The bispecific antibody inhibits heregulin activation of ErbB2 and ErbB3, and the co-administration creates a substantially superadditive effect.
The method optionally includes an effective amount of trastuzumab or ado-trastuzumab emtansine as part of the co-administration regimen. The approach addresses avoiding drug-drug interaction–mediated toxicity while achieving enhanced inhibition outcomes.
Supportive preclinical evidence is described, including in vivo tumor growth inhibition in BT474-M3 estrogen/heregulin-driven models using MM-111 together with tamoxifen or lapatinib, along with enhanced apoptosis and stronger suppression of heregulin-driven ErbB3/pAKT signaling compared with lapatinib alone.
Claims Coverage
The provided claims include one independent claim centered on co-administration of trametinib and a bispecific anti-ErbB2/anti-ErbB3 antibody to treat a subject with a malignant tumor, with a substantially superadditive effect. Dependent claims further specify optional trastuzumab or ado-trastuzumab emtansine, avoidance of drug-drug interaction–mediated toxicity, antibody definition by SEQ ID NO:1, optional capecitabine and/or cisplatin, and limiting the subject to humans.
Substantially superadditive co-administration with trametinib
Co-administering an effective amount of trametinib with a bispecific anti-ErbB2/anti-ErbB3 antibody that inhibits heregulin activation of ErbB2 and ErbB3 to treat a subject with a malignant tumor, wherein the co-administration creates a substantially superadditive effect.
Bispecific antibody inhibits heregulin activation of ErbB2 and ErbB3
Using a bispecific anti-ErbB2/anti-ErbB3 antibody that inhibits heregulin activation of ErbB2 and ErbB3 as part of the treating method.
Optional trastuzumab or ado-trastuzumab emtansine co-administration
Optionally co-administering an effective amount of trastuzumab or ado-trastuzumab emtansine together with trametinib and the bispecific anti-ErbB2/anti-ErbB3 antibody.
Avoiding drug-drug interaction–mediated toxicity
Co-administering the agents to the subject without causing drug-drug interaction–mediated toxicity.
Antibody comprises the amino acid sequence of SEQ ID NO:1
Using a bispecific anti-ErbB2/anti-ErbB3 antibody that comprises the amino acid sequence of SEQ ID NO:1.
Optional concomitant capecitabine and/or cisplatin
Optionally further administering an effective amount of capecitabine and/or cisplatin as part of the method.
Human as the subject
Performing the method with a human as the subject.
Overall, the claim set centers on trametinib plus a bispecific anti-ErbB2/anti-ErbB3 antibody that inhibits heregulin activation of ErbB2 and ErbB3 and yields a substantially superadditive effect. Dependent claim coverage further adds optional trastuzumab or ado-trastuzumab emtansine, a toxicity-related limitation, SEQ ID NO:1, optional capecitabine and/or cisplatin, and humans as the subject.
Stated Advantages
Achieves substantially superadditive (greater-than-additive) inhibition.
Avoids drug-drug interaction–mediated toxicity.
Documented Applications
Treatment of a subject with a malignant tumor using co-administration of trametinib and a bispecific anti-ErbB2/anti-ErbB3 antibody that inhibits heregulin activation of ErbB2 and ErbB3, optionally with trastuzumab or ado-trastuzumab emtansine.
Supportive preclinical use in BT474-M3 estrogen/heregulin-driven models showing tumor growth inhibition and stronger suppression of heregulin-driven ErbB3/pAKT signaling, including combination with tamoxifen or lapatinib.
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