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Combination/adjuvant therapy for WT-1-positive disease

One-WT-1, composition technology, applied in the field of combined/adjuvant therapy for WT‑1‑positive diseases, capable of solving problems such as limited and refractory diseases

Inactive Publication Date: 2016-11-30
MEMORIAL SLOAN KETTERING CANCER CENT
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the clinical efficacy of some TKIs (eg, imatinib and sunitinib) is limited by the rare development of patient-specific drug intolerance or treatment-refractory disease

Method used

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  • Combination/adjuvant therapy for WT-1-positive disease
  • Combination/adjuvant therapy for WT-1-positive disease
  • Combination/adjuvant therapy for WT-1-positive disease

Examples

Experimental program
Comparison scheme
Effect test

Embodiment approach

[0162] 1. A pharmaceutical composition comprising a tyrosine kinase inhibitor (TKI); and

[0163] (A) an antibody comprising a heavy chain (HC) variable region and a light chain (LC) variable region, the heavy chain (HC) variable region comprising HC-CDR1, HC-CDR2, and HC-CDR3, and the The light chain (LC) variable region comprises LC-CDR1, LC-CDR2 and LC-CDR3, and the heavy chain (HC) variable region and light chain (LC) variable region comprise Tables 1-14 and Figure 7-10 the amino acid sequence shown in; or

[0164] (B) contains V H and V L antibody, the V H and V L comprising a first amino acid sequence and a second amino acid sequence from Tables 1-12; or

[0165] (C) Antibodies comprising scFv comprising amino acid sequences from Tables 1-12.

[0166] 2. The pharmaceutical composition of embodiment 1, wherein the tyrosine kinase inhibitor is selected from the group consisting of imatinib, dasatinib, nilotinib, bosutinib, Natinib, bafetinib, erlotinib, gefitinib, l...

Embodiment 1

[0190] Materials and methods

[0191] Cell samples, cell lines and antibodies. Peripheral blood sheets were obtained from HLA-type healthy donors and patients by Ficoll density gradient centrifugation after signed informed consent on a protocol approved by the Sloan-Kettering Cancer Center Institutional Review Board nuclear cells (PBMC). All cells were HLA-typed by the Cellular Immunology Department of Memorial Sloan-Kettering Cancer Center. The leukemia cell line BV173 (WT-1+, A0201+) was a gift from Dr. H.J. Stauss (University College London, London, United Kingdom). at 37°C / 5% CO 2 Next, the cell lines were cultured in RPMI 1640 supplemented with 5% FCS, penicillin, streptomycin, 2mmol / L glutamine and 2-mercaptoethanol.

[0192] animal. Six- to eight-week-old male NOD.Cg-Prkdc scid IL2rgtm1Wjl / SzJ mice, designated NOD / SCIDγ (NSG), were purchased from the Jackson Laboratory (Bar Harbor, ME) or obtained from the MSKCC animal husbandry facility.

[0193] Transduction and...

Embodiment 2

[0195] Antibody-dependent cellular cytotoxicity (ADCC)

[0196] ADCC is considered to be one of the major effector mechanisms of therapeutic human mAbs. Therefore, the evaluation of efficacy began with an in vitro assay measuring ADCC against the BV173 cell line derived from CML at risk. Fresh BV173 cells were used for ADCC target cells. WT-1 antibody or its isotype control human IgG1 were incubated with target cells and fresh PBMCs at 750 ng / ml at different effector:target (E:T) ratios for 6 hours. Imatinib was added at concentrations of 0, 1, 5 and 10 μM. Supernatants were harvested and cytotoxicity was measured by standard Chromium 51 release assay.

[0197] In the presence of human PBMCs, WT-1 antibody mediates dose-dependent PBMCADCC against naturally presented RMF epitopes by HLA-A0201 molecules on tumor cells (leukemic cell line BV173). Importantly, WT-1 antibody was able to mediate ADCC in the presence of different doses of imatinib. Using PBMC from multiple healt...

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Abstract

In an attempt to improve primary disease responsiveness and / or to overcome resistant disease, the present disclosure provides a method for treating or inhibiting the proliferation of a WT-1 -dependent cancer comprising providing to a subject in need thereof a therapeutically effective amount of a tyrosine kinase inhibitor along with an anti-WT-1 / HLA antibody, that is, an antibody that specifically binds to a peptide of Wilms' tumor protein (WT-1 ) presented on the surface of the cancer cells in an HLA-restricted fashion.

Description

[0001] Cross References to Related Applications [0002] This application contains subject matter related to that of: Commonly assigned PCT International Application Serial No. PCT / US2012 / 031892, filed 2 April 2012, entitled "T-Cell Receptor Like Antibodies Specific for WT1 Peptides" and filed 2013 Commonly assigned U.S. Provisional Application No. 61 / 798,563, entitled "Antibodies to Cytosolic Peptides" (Attorney Docket No. 3314.030P), filed March 15, 2009; the contents of each of which are hereby incorporated by reference in their entirety. [0003] It is hereby declared that U.S. Provisional Patent Application Serial No. 61 / 794,168, filed March 15, 2013, and U.S. Provisional Patent Application Serial No. 61 / 880,585, filed September 20, 2013, under 35 U.S.C. § 119(e) interest, and the disclosures of both priority documents are incorporated herein by reference in their entirety. [0004] Statement of Rights for Federally Sponsored Research [0005] This invention was made with...

Claims

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Application Information

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IPC IPC(8): A61K39/395A61K45/06A61K31/506A61K31/519A61P35/00A61P35/02
Inventor D·沙因伯格L·都伯夫斯基
Owner MEMORIAL SLOAN KETTERING CANCER CENT
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