Mutant smoothened and methods of using the same

A technology of antibodies and amino acids, applied in the field of smooth mutants and its use, can solve the problems of drug resistance in patients

Inactive Publication Date: 2018-12-21
CURIS INC +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, it is unclear which mechanism drives resistance in patients

Method used

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  • Mutant smoothened and methods of using the same
  • Mutant smoothened and methods of using the same
  • Mutant smoothened and methods of using the same

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[0343] 5. Preparation of antibody-drug conjugates

[0344] In an antibody drug conjugate (ADC), an antibody (Ab) is conjugated to one or more drug moieties (D) via a linker (L), for example about 1 to about 20 drug moieties per antibody (p=1 to about 20). ADCs of the formula shown below can be prepared in several ways using organic chemistry reactions, conditions, and reagents known to those skilled in the art, including: (1) reacting the nucleophilic group of the antibody with a divalent linker, thereby utilizing a covalent A valent bond to form Ab-L, followed by reaction with the drug moiety D; and (2) reaction of the nucleophilic group of the drug moiety with a divalent linker, using a covalent bond to form D-L, followed by reaction with the nucleophilic group of the antibody. Additional methods for preparing ADCs are described herein.

[0345] Ab-(L-D) p

[0346] A linker may consist of one or more linker components. Exemplary linker components include: 6-maleimidocap...

example

[0485] Now that the present disclosure is generally described, it will be more readily understood by reference to the following examples, which are presented for purposes of illustration of certain aspects and embodiments of the disclosure and are not intended to limit the disclosure.

example 1

[0486] Example 1: Mutation analysis of vismodegib-resistant basal cell carcinoma.

[0487] Clinical responses to targeted therapies (eg, cancer therapy) can be transient due to the acquisition of genetic alterations that confer drug resistance. Identification of resistance mechanisms will guide novel therapeutic strategies. Inappropriate Hh signaling has been linked to several cancers, including basal cell carcinoma (BCC). Loss-of-function mutations in PTCH (about 90%) and activating mutations in SMO (about 10%) are the main pathogenic factors of BCC. By using FoundationOne TM A next-generation sequencing (NGS) platform was used to assess vimodeji sensitivity and the mutation status of patients' BCC to identify clinical mechanisms of resistance to vimodeji (GDC-0449). figure 1 The characteristics of patients with mBCC (metastatic basal cell carcinoma) treated with Vimodeji are listed.

[0488] as in figure 2As shown in , the median exon coverage for each tumor biopsy spe...

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Abstract

The emergence of mutations in tyrosine kinases following treatment of cancer patients with molecular-targeted therapy represents a major mechanism of acquired drug resistance. Here, mutations in the serpentine receptor, Smoothened (SMO) are described, which result in resistance to a Hedgehog (Hh) pathway inhibitor, such as in medulloblastoma. Amino acid substitutions in conserved residues of SMO maintain Hh signaling, but result in the inability of the Hh pathway inhibitor, GDC-0449, to suppress the pathway. In some embodiments, the disclosure provides for novel mutant SMO proteins and nucleicacids and for screening methods to detect SMO mutations and methods to screen for drugs that specifically modulate mutant SMO exhibiting drug resistance.

Description

technical field [0001] This application claims priority to US Provisional Patent Application Serial No. 62 / 291,346, filed February 4, 2016. The disclosures of the aforementioned applications are incorporated herein by reference in their entirety. Background technique [0002] Molecularly targeted cancer therapy has shown strong activity in the clinic. Some of the most notable examples include the tyrosine kinase inhibitor imatinib in Philadelphia chromosome-positive chronic myelogenous leukemia (CML) or kit / PDGFR-mutant gastrointestinal stromal tumor (GIST) and EGFR Erlotinib in mutant non-small cell lung cancer (NSCLC) (Krause, D.S. and R.A. Van Etten (2005) N. Engl. J. Med 353(2):172-187) . Treatment with these agents has produced dramatic antitumor responses in patient populations with these molecular abnormalities. However, despite impressive initial clinical responses, most patients eventually develop disease due to the development of drug resistance (Engelman, J.A....

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K14/705
CPCC07K14/705A61P35/00C12N15/62A61K47/6851G01N33/5011G01N2333/726G01N2500/04G01N2500/10
Inventor 海莉·夏普史蒂文·让德罗
Owner CURIS INC
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