51 results about "Trastuzumab resistance" patented technology

Cell-targeted serine protease constructs are provided. Such constructs can be used in methods for targeted cell killing such as for treatment cell of proliferative diseases (e.g., cancer). In some aspects, recombinant serine proteases, such as Granzyme B polypeptides, are provided that exhibit improved stability and cell toxicity. Methods and compositions for treating lapatinib or trastuzumab-resistant cancers are also provided.

The expression of Her-2 / neu protein on circulating cancer cells in a blood sample is detected by isolating the cancer cells from the blood sample and then performing on the isolated cancer cells a sensitive Her-2 / neu immunoassay. A positive result indicates the expression of Her-2 / neu on cancer cells in the blood sample. This method can be used to identify cancer patients who are likely to benefit from treatment with an anticancer agent that targets Her-2 / neu, such as trastuzumab (HERCEPTIN).

The present disclosure relates to bispecific antibodies targeting EGFR and HER2, and methods for the production of these antibodies. The bispecific antibodies consist of one complete antibody on whichtwo VH-VL chains are attached via a linker to each NH terminal region of both VH chains of the antibody. The bispecific antibodies constructed use the amino acid sequences of the heavy chain (VH) andthe light chain (VL) variable regions of two monoclonal antibodies targeting EGFR and HER2, namely cetuximab and trastuzumab, respectively

A combination of temsirolimus and trastuzumab in the treatment of cancer is provided. A combination of temsirolimus and HKI-272 is provided. A combination of a trastuzumab and a HKI-272 is also provided. Regimens and kits for treatment of metastatic breast cancer, containing trastuzumab, temsirolimus and / or HKI-272, optionally in combination with other anti-neoplastic agents, or immune modulators are described.

A combination of temsirolimus and trastuzumab in the treatment of cancer is provided. A combination of temsirolimus and HKI-272 is provided. A combination of a trastuzumab and a HKI-272 is also provided. Regimens and kits for treatment of metastatic breast cancer, containing trastuzumab, temsirolimus and / or HKI-272, optionally in combination with other anti-neoplastic agents, or immune modulators are described.

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.

Methods for the treatment of patients with HER2-positive, HER2-amplified and / or HER2-mutated advanced cancer by administration of pertuzumab plus trastuzumab are disclosed. In one aspect, the cancer is advanced HER2-positive, HER2-amplified and / or HER2-mutated colorectal, biliary, bladder, urothelial, salivary, lung, pancreatic, ovarian, prostate, or skin cancer. In another aspect, the cancer is HER2-positive, HER2-amplified and / or HER2-mutated colorectal, biliary, bladder, urothelial, salivary, lung, pancreatic, ovarian, prostate, or skin cancer that is refractory to one or more other treatment regimens.

Disclosed herein are methods of treating cancer in a patient, the method comprising identifying a patient who is resistant to treatment with an anti-HER2 therapy; and administering to the patient a drug delivery molecule, comprising a polypeptide molecule adapted to target and / or penetrate a type of cell; a nucleic acid molecule bound to the polypeptide sequence via electrostatic interactions; and a chemical agent non-covalently linked to the nucleic acid sequence. Also disclosed are methods of inducing apoptosis in an anti-HER2 therapy resistant HER2+ breast cancer cell, the method comprising contacting the anti-HER2 therapy resistant HER2+ breast cancer cell with the drug delivery molecule. Further disclosed herein are methods of treating cancer in a patient, the method comprising identifying a patient who is resistant to anti-HER2 therapy; and administering to the patient a therapeutically effective amount of a drug delivery molecule, comprising a polypeptide molecule adapted to target and / or penetrate a type of cell; and a sulfonated corrole molecule bound to the polypeptide sequence. Finally disclosed herein are methods of inducing apoptosis in an anti-HER2 therapy resistant HER2+ breast cancer cell, the method comprising contacting the anti-HER2 therapy resistant HER2+ breast cancer cell with a drug delivery molecule, comprising a polypeptide molecule adapted to target and / or penetrate a type of cell; and a sulfonated corrole molecule bound to the polypeptide sequence.

Methods are provided for the adjuvant treatment of operable HER2-positive primary breast cancer in human patients by administration of pertuzumab in addition to chemotherapy and trastuzumab. The methods reduce the risk of recurrence of invasive breast cancer or death for a patient diagnosed with HER2-positive early breast cancer (eBC) compared to administration of trastuzumab and chemotherapy, without pertuzumab.

Cell-targeted serine protease constructs are provided. Such constructs can be used in methods for targeted cell killing such as for treatment cell of proliferative diseases (e.g., cancer). In some aspects, recombinant serine proteases, such as Granzyme B polypeptides, are provided that exhibit improved stability and cell toxicity. Methods and compositions for treating lapatinib or trastuzumab-resistant cancers are also provided.

Methods are provided for the adjuvant treatment of operable HER2-positive primary breast cancer in human patients by administration of pertuzumab in addition to chemotherapy and trastuzumab. The methods reduce the risk of recurrence of invasive breast cancer or death for a patient diagnosed with HER2-positive early breast cancer (eBC) compared to administration of trastuzumab and chemotherapy, without pertuzumab.

The invention provides a cell strain for expressing HER2 gene, and a construction method and application thereof. The method comprises the following steps: 1) inserting HER2 gene into the polyclone site of the expression vector to obtain a recombinant expression vector; and 2) transfecting a cell strain by using the recombinant expression vector to obtain the monoclonal cell strain for expressing HER2 gene. The cell strain can efficiently and stably express the HER2 gene, has resistance to the existing HER2 targeted antibody drug trastuzumab, can successfully construct a human breast cancer transplantation tumor model in the nude mouse body, and can be used for screening novel breast cancer drugs.

The invention relates to medicine technical field, and particularly relates to a preparation method of a trastuzumab-mediated cis-platinum targeting conjugate and application of the trastuzumab-mediated cis-platinum targeting conjugate in the preparation of a breast cancer resistant drug. Amphiphilic block copolymer methoxy polyethylene glycol-polyglutamic acid (mPEG-PGA) prepared from methoxypolyethylene glycol amine and 5-benzyl L-glutamate N-carboxyanhydrie is used as a base material for preparation of cis-platinum loading nano balls through the membrane dialysis method, and a carrier is connected with trastuzumab by carrier surface carboxyl group to prepare the trastuzumab-mediated cis-platinum targeting conjugate. The trastuzumab-mediated cis-platinum targeting conjugate can be targeted to enrich chemotherapy drugs in tumor site so as to directly kill tumor cells, reduce the side and toxic effects of traditional antitumor drugs, and trastuzumab targeting therapy of HER2 positive breast cancer patients can be implemented. The trastuzumab-mediated cis-platinum targeting conjugate can cleverly realize trastuzumab and cis-platinum combined targeted drug delivery way, and has good application prospect in treatment of breast cancer by combination of trastuzumab and chemotherapy.

The invention discloses a method for knocking out an FUT8 gene to improve the ADCC activity of an antibody. And coding the FUT8 gene of the CHO cell by using a CRISPR / Cas9 technology to obtain the CHO cell silenced by the FUT8 gene. Through detection of physicochemical properties and biological activity of the engineered cell expression antibody, a glycoform detection result shows that fucose of the engineered cell expression antibody is completely eliminated, and by taking trastuzumab as a contrast, the affinity of the engineered cell expression complete fucose-free antibody and Fc gamma Rs antigen is improved by 20 times, and the ADCC effect is improved by 19 times.

Contemplated immunotherapies include co-administration of an activated NK cell that is further genetically modified and a cancer therapeutic agent. In preferred embodiments, activated NK cells are further modified to taNK cells, which include a chimeric antigen receptor (CAR) with affinity for a cancer specific antigen, a cancer associated antigen, or a tumor specific antigen. Activated NK cells can also be further genetically modified to include high affinity Fc receptor CD16a (V158). Appropriate cancer therapeutic agents include chemotherapeutic drugs (e.g., nant-paclitaxel) or cancer targeted antibodies (e.g., trastuzumab).

The disclosed method rapidly identifies with desired accuracy AML patients, including elderly AML patients, likely to respond to treatment with a combination of a farnesyltransferase inhibitor and one or more of etoposide, teniposide, tamoxifen, sorafenib, paclitaxel, temozolomide, topotecan, trastuzumab and cisplatinum. In an embodiment, the improvements include the use of whole blood rather than the customary bone marrow sample, thus making the assay more accurate, rapid, less intrusive, less expensive as well as less painful. The method includes evaluation of a two-gene expression ratio (RASGRP1 :APTX), which with a corresponding threshold, provides sufficient accuracy for predicting the response to the combination treatment. In the preferred embodiment the combination treatment combines tipifarnib (Rl 15777, ZARNESTRA TM ) with etoposide. Further, the elderly AML patients identified as being likely responsive to the combination treatment with tipinifarb and etoposide have a complete recovery rate comparable to the best therapy available for younger patients.

The present invention relates to a novel anti-HER2 antibody or antigen-binding fragment thereof used in the prevention or treatment of cancer, a chimeric antigen receptor comprising the same, and usesthereof. The antibody of the present invention is an antibody that specifically binds to HER2 which is highly expressed in cancer cells (particularly, breast cancer or gastric cancer cells), and binds to an epitope that is different from an epitope to which conventional trastuzumab binds. Compared to transtuzumab, the antibody of the present invention exhibits a better killing ability with respect to kill HER2-unexpressed cancer cells which have non reactivity (or resistance) to a trastuzumab antibody or have reduced sensitivity. In addition, when the anti-HER2 antibody of the present invention is administered in combination with trastuzumab, a synergistic killing ability with respect to a cancer cell line on which the trastuzumab antibody acts. Therefore, a composition of the present invention can be very usefully used for combined administration with a trastuzumab antibody for the treatment of cancer, and for the treatment of cancer not treated by trastuzumab.

The present disclosure relates to bispecific antibodies targeting EGFR and HER2, and methods for the production of these antibodies. The bispecific antibodies consist of one complete antibody on which two VH-VL chains are attached via a linker to each NH terminal region of both VH chains of the antibody. The bispecific antibodies constructed use the amino acid sequences of the heavy chain (VH) and the light chain (VL) variable regions of two monoclonal antibodies targeting EGFR and HER2, namely cetuximab and trastuzumab, respectively.

The present invention found that lasofoxifene is an antagonist of ER-α36. It not only inhibits the growth of ER-α36 positive lung, colon and gastric cancers, and also it can inhibit the growth of acquired or de novo tamoxifen-resistant MCF-7 cells. Our finding also provides methods and compositions for treating cancer comprising lasofoxifene alone or in combination with at least one other agent selected from the group consisting of gefitinib and / or trastuzumab or functional equivalent thereof, and an inhibitor in hormonal or epidermal growth factor signal transduction pathways.

A system and method for using a concomitant effect of cold atmospheric plasma and Trastuzumab to overcome Trastuzumab invalidity or resistance and enhances the outcome of breast cancer therapy in both HER2-positive and negative cancer cells.

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 either i) an effective amount of an anti-estrogen agent or ii) an effective amount of a receptor tyrosine kinase inhibitor and an effective amount of a bispecific anti-ErbB2 / anti-ErbB3 antibody, and optionally an effective amount of trastuzumab. Also disclosed is a bispecific anti-ErbB2 / anti-ErbB3 antibody for use in the therapy of a tumor in combination with either i) an anti-estrogen agent or ii) a receptor tyrosine kinase inhibitor, and optionally in use with trastuzumab.

This invention relates to a composition and a method for prediction of a response to Trastuzumab therapy in a breast cancer patient, and more specifically, a composition, a kit, a DNA chip, and a method for predicting a response to Trastuzumab therapy by using polynucleotides each comprising a nucleotide sequence represented by any of SEQ ID NOs: 1 to 9, 11 to 19, and 21 to 23 in the Sequence Listing or a nucleotide sequence derived therefrom by substitution of u with t, mutants thereof, derivatives thereof, or fragments thereof comprising at least 16 continuous nucleotides, or a polynucleotide comprising a complementary sequence thereof, and using an increase or decrease in Her2 protein expression level as an indicator.

The present disclosure relates to a novel anti-HER2 antibody or an antigen-binding fragment thereof used in the prevention or treatment of cancer, a chimeric antigen receptor including the same, and uses thereof. The antibody of the present disclosure is an antibody that specifically binds to HER2 which is highly expressed in cancer cells (particularly, breast cancer or gastric cancer cells), and binds to an epitope that is different from an epitope to which trastuzumab binds. When compared with trastuzumab, the antibody of the present disclosure exhibits better killing ability for HER2-unexpressed cancer cells which have non-reactivity (or resistance) to the trastuzumab antibody or have reduced sensitivity. In addition, when the anti-HER2 antibody of the present disclosure is administered in combination with trastuzumab, a synergistic killing ability is achieved for cancer cells on which the trastuzumab antibody acts. Therefore, a composition of the present disclosure can be very usefully used for combined administration with the trastuzumab antibody for the treatment of cancer, or for the treatment of cancer not treated with trastuzumab.

This disclosure relates to methods of generating antibody libraries, antibody libraries produced using such methods, and variant antibodies. Presently, methods of improving antibody binding (affinity maturation assays) require the screening of vast libraries of antibody variants (often >1010) to identify a small fraction of variants with improved characteristics. The present invention involves taking the nucleotide sequence of the framework and complementarity determining region of a target antibody and identifying motifs which would be recognised by deamination somatic hypermutation enzymes. A small library of variants is then created which incorporate one or more of these mutations. It was found that a relatively high proportion of the variants have an increased affinity. The technique of the present invention was demonstrated on the trastuzumab and Cathepsin S antibodies, and the variants produced are also claimed.

The invention discloses a gene mutation site for predicting the anti-HER2 therapeutic drug reactivity of patients with breast cancer and application thereof. By a large scale of screening, the inventor discovers for the first time that the 3020 site of the HER2 gene coding sequence is related to the drug reactivity of patients with breast cancer on trastuzumab, lapatinib or pyrotinib. Based on theresearch result, a product for predicting the drug reactivity of a patient with breast cancer on trastuzumab, lapatinib or pyrotinib is developed. The product can be widely applied to clinical application by detecting the function of the 3020 site genome of the HER2 gene coding sequence.

Provided are p97 (melanotransferrin)-trastuzumab fusion proteins and related methods of use thereof, for instance, to facilitate delivery of trastuzumab across the blood-brain barrier (BBB) and / or improve tissue penetration of the antibody in CNS and peripheral tissues, and thereby treat and / or diagnose HER2-positive cancers, including those of the central nervous system (CNS).

Antibody-drug-conjugates (ADC) are provided having a structure of:wherein L is PR3 ligand. The ADC has n drug moieties bound to the Trastuzumab antibody such that the ADC has a drug-to-antibody ratio (DAR) between 2 and 4 and the drug moieties are bound to the Trastuzumab antibody through cysteine (S) or lystine (Lys) residues. The disclosed ADCs are particularly useful in treating breast cancer.

The invention relates to a construction method of an HER2 positive gastric cancer drug-resistant PDX model, which comprises the step of transplanting fresh gastric cancer tissues of a drug-resistant HER2 positive gastric cancer patient after drug treatment to the subcutaneous part of a mouse. The gastric cancer tissue of the drug-resistant patient treated by HER2 positive trastuzumab is clinically obtained, and the gastric cancer PDX model is successfully established. The scheme provided by the invention plays a crucial role in understanding a potential molecular mechanism of acquired drug resistance of trastuzumab, searching a new treatment strategy for overcoming drug resistance and formulating a next effective treatment scheme.

The present invention provides methods of treating of HER2-positive cancers (such as HER2-positive breast cancer and HER2-positive gastric cancers) using HER2 antibodies, such as a combination of a HER2 T cell-dependent bispecific antibody (TDB) with an additional HER2 antibody (e.g., trastuzumab).