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10.1080/19420862.2018.1426421 http://scihub22266oqcxt.onion/10.1080/19420862.2018.1426421 C5916551!5916551 !29333938     free     free     free Warning: file_get_contents(https://eutils.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&id=29333938 &cmd=llinks): Failed to open stream: HTTP request failed! HTTP/1.1 429 Too Many Requests in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 215 Deprecated: Implicit conversion from float 211.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 211.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 211.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 211.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 211.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 211.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 211.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 211.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Warning: imagejpeg(C:\Inetpub\vhosts\kidney.de\httpdocs\phplern\29333938 .jpg): Failed to open stream: No such file or directory in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 117       MAbs 2018 ; 10 (3 ): 444-452 Nephropedia Template TP {{tp|p=29333938 |t=2018. Structure-based engineering to restore high affinity binding of an isoform-selective anti-TGF?1 antibody |pdf=|usr=}}{{29333938 }} gab.com Text Structure-based engineering to restore high affinity binding of an isoform-selective anti-TGF 1 antibody JO: MAbs http://www.kidney.de/pget.php?&tw=1&pmid=29333938 #FOAvip Metelimumab (CAT192) is a human IgG4 monoclonal antibody developed as a TGF?1-specific antagonist. It was tested in clinical trials for the treatment of scleroderma but later terminated due to lack of efficacy. Subsequent characterization of CAT192 indicated that its TGF?1 binding affinity was reduced by ?50-fold upon conversion from the parental single-chain variable fragment (scFv) to IgG4. We hypothesized this result was due to decreased conformational flexibility of the IgG that could be altered via engineering. Therefore, we designed insertion mutants in the elbow region and screened for binding and potency. Our results indicated that increasing the elbow region linker length in each chain successfully restored the isoform-specific and high affinity binding of CAT192 to TGF?1. The crystal structure of the high binding affinity mutant displays large conformational rearrangements of the variable domains compared to the wild-type antigen-binding fragment (Fab) and the low binding affinity mutants. Insertion of two glycines in both the heavy and light chain elbow regions provided sufficient flexibility for the variable domains to extend further apart than the wild-type Fab, and allow the CDR3s to make additional interactions not seen in the wild-type Fab structure. These interactions coupled with the dramatic conformational changes provide a possible explanation of how the scFv and elbow-engineered Fabs bind TGF?1 with high affinity. This study demonstrates the benefits of re-examining both structure and function when converting scFv to IgG molecules, and highlights the potential of structure-based engineering to produce fully functional antibodies. Twit Text FOAVip Structure-based engineering to restore high affinity binding of an isoform-selective anti-TGF 1 antibody ????MAbs http://www.kidney.de/pget.php?&tw=1&pmid=29333938 #FOAvip Twit Text # Free Paper on # # # # # LINK http://www.kidney.de/pget.php?&tw=1&pmid=29333938 #FOAvip English Wikipedia <ref>{{Cite pmid|29333938 }}</ref> Structure-based engineering to restore high affinity binding of an isoform-selective anti-TGF?1 antibody #MMPMID29333938 Lord DM ; Bird JJ ; Honey DM ; Best A ; Park A ; Wei RR ; Qiu H MAbs 2018[Apr]; 10 (3 ): 444-452 PMID29333938 show ga Metelimumab (CAT192) is a human IgG4 monoclonal antibody developed as a TGF?1-specific antagonist. It was tested in clinical trials for the treatment of scleroderma but later terminated due to lack of efficacy. Subsequent characterization of CAT192 indicated that its TGF?1 binding affinity was reduced by ?50-fold upon conversion from the parental single-chain variable fragment (scFv) to IgG4. We hypothesized this result was due to decreased conformational flexibility of the IgG that could be altered via engineering. Therefore, we designed insertion mutants in the elbow region and screened for binding and potency. Our results indicated that increasing the elbow region linker length in each chain successfully restored the isoform-specific and high affinity binding of CAT192 to TGF?1. The crystal structure of the high binding affinity mutant displays large conformational rearrangements of the variable domains compared to the wild-type antigen-binding fragment (Fab) and the low binding affinity mutants. Insertion of two glycines in both the heavy and light chain elbow regions provided sufficient flexibility for the variable domains to extend further apart than the wild-type Fab, and allow the CDR3s to make additional interactions not seen in the wild-type Fab structure. These interactions coupled with the dramatic conformational changes provide a possible explanation of how the scFv and elbow-engineered Fabs bind TGF?1 with high affinity. This study demonstrates the benefits of re-examining both structure and function when converting scFv to IgG molecules, and highlights the potential of structure-based engineering to produce fully functional antibodies. |*Antibody Affinity [MESH] |*Protein Engineering [MESH] |A549 Cells [MESH] |Crystallography, X-Ray [MESH] |Humans [MESH] |Immunoglobulin G/*chemistry/genetics [MESH] |Protein Domains [MESH] |Single-Chain Antibodies/*chemistry/genetics [MESH]Structure-based engineering to restore high affinity binding of an i(epmc).pdf DeepDyve Pubget Overpricing