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28 results on '"Haidar, Jaafar N."'

1. Therapeutic high affinity T cell receptor targeting a KRASG12D cancer neoantigen

Author

Poole, Andrew, Karuppiah, Vijaykumar, Hartt, Annabelle, Haidar, Jaafar N., Moureau, Sylvie, Dobrzycki, Tomasz, Hayes, Conor, Rowley, Christopher, Dias, Jorge, Harper, Stephen, Barnbrook, Keir, Hock, Miriam, Coles, Charlotte, Yang, Wei, Aleksic, Milos, Lin, Aimee Bence, Robinson, Ross, Dukes, Joe D., Liddy, Nathaniel, Van der Kamp, Marc, Plowman, Gregory D., Vuidepot, Annelise, Cole, David K., Whale, Andrew D., and Chillakuri, Chandramouli

Published
2022
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2. Supplementary Data File from Bispecific Targeting of PD-1 and PD-L1 Enhances T-cell Activation and Antitumor Immunity

Author

Kotanides, Helen, primary, Li, Yiwen, primary, Malabunga, Maria, primary, Carpenito, Carmine, primary, Eastman, Scott W., primary, Shen, Yang, primary, Wang, George, primary, Inigo, Ivan, primary, Surguladze, David, primary, Pennello, Anthony L., primary, Persaud, Krishnadatt, primary, Hindi, Sagit, primary, Topper, Michael, primary, Chen, Xinlei, primary, Zhang, Yiwei, primary, Bulaon, Danielle K., primary, Bailey, Tim, primary, Lao, Yanbin, primary, Han, Bing, primary, Torgerson, Stacy, primary, Chin, Darin, primary, Sonyi, Andreas, primary, Haidar, Jaafar N., primary, Novosiadly, Ruslan D., primary, Moxham, Christopher M., primary, Plowman, Gregory D., primary, Ludwig, Dale L., primary, and Kalos, Michael, primary

Published
2023
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3. Data from Bispecific Targeting of PD-1 and PD-L1 Enhances T-cell Activation and Antitumor Immunity

Author

Kotanides, Helen, primary, Li, Yiwen, primary, Malabunga, Maria, primary, Carpenito, Carmine, primary, Eastman, Scott W., primary, Shen, Yang, primary, Wang, George, primary, Inigo, Ivan, primary, Surguladze, David, primary, Pennello, Anthony L., primary, Persaud, Krishnadatt, primary, Hindi, Sagit, primary, Topper, Michael, primary, Chen, Xinlei, primary, Zhang, Yiwei, primary, Bulaon, Danielle K., primary, Bailey, Tim, primary, Lao, Yanbin, primary, Han, Bing, primary, Torgerson, Stacy, primary, Chin, Darin, primary, Sonyi, Andreas, primary, Haidar, Jaafar N., primary, Novosiadly, Ruslan D., primary, Moxham, Christopher M., primary, Plowman, Gregory D., primary, Ludwig, Dale L., primary, and Kalos, Michael, primary

Published
2023
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4. Data from Characterization of 7A5: A Human CD137 (4-1BB) Receptor Binding Monoclonal Antibody with Differential Agonist Properties That Promotes Antitumor Immunity

Author

Kotanides, Helen, primary, Sattler, Rose Marie, primary, Lebron, Maria B., primary, Carpenito, Carmine, primary, Shen, Juqun, primary, Li, Jingxing, primary, Surguladze, David, primary, Haidar, Jaafar N., primary, Burns, Colleen, primary, Shen, Leyi, primary, Inigo, Ivan, primary, Pennello, Anthony L., primary, Forest, Amelie, primary, Chen, Xinlei, primary, Chin, Darin, primary, Sonyi, Andreas, primary, Topper, Michael, primary, Boucher, Lauren, primary, Sharma, Prachi, primary, Zhang, Yiwei, primary, Burtrum, Douglas, primary, Novosiadly, Ruslan D., primary, Ludwig, Dale L., primary, Plowman, Gregory D., primary, and Kalos, Michael, primary

Published
2023
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5. Figure S9 from Characterization of 7A5: A Human CD137 (4-1BB) Receptor Binding Monoclonal Antibody with Differential Agonist Properties That Promotes Antitumor Immunity

Author

Kotanides, Helen, primary, Sattler, Rose Marie, primary, Lebron, Maria B., primary, Carpenito, Carmine, primary, Shen, Juqun, primary, Li, Jingxing, primary, Surguladze, David, primary, Haidar, Jaafar N., primary, Burns, Colleen, primary, Shen, Leyi, primary, Inigo, Ivan, primary, Pennello, Anthony L., primary, Forest, Amelie, primary, Chen, Xinlei, primary, Chin, Darin, primary, Sonyi, Andreas, primary, Topper, Michael, primary, Boucher, Lauren, primary, Sharma, Prachi, primary, Zhang, Yiwei, primary, Burtrum, Douglas, primary, Novosiadly, Ruslan D., primary, Ludwig, Dale L., primary, Plowman, Gregory D., primary, and Kalos, Michael, primary

Published
2023
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6. Table S1 from Characterization of 7A5: A Human CD137 (4-1BB) Receptor Binding Monoclonal Antibody with Differential Agonist Properties That Promotes Antitumor Immunity

Author

Kotanides, Helen, primary, Sattler, Rose Marie, primary, Lebron, Maria B., primary, Carpenito, Carmine, primary, Shen, Juqun, primary, Li, Jingxing, primary, Surguladze, David, primary, Haidar, Jaafar N., primary, Burns, Colleen, primary, Shen, Leyi, primary, Inigo, Ivan, primary, Pennello, Anthony L., primary, Forest, Amelie, primary, Chen, Xinlei, primary, Chin, Darin, primary, Sonyi, Andreas, primary, Topper, Michael, primary, Boucher, Lauren, primary, Sharma, Prachi, primary, Zhang, Yiwei, primary, Burtrum, Douglas, primary, Novosiadly, Ruslan D., primary, Ludwig, Dale L., primary, Plowman, Gregory D., primary, and Kalos, Michael, primary

Published
2023
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7. Supplementary Tables S1-S4 and Supplementary Figures S1-S6 from Molecular Basis for Necitumumab Inhibition of EGFR Variants Associated with Acquired Cetuximab Resistance

Author

Bagchi, Atrish, primary, Haidar, Jaafar N., primary, Eastman, Scott W., primary, Vieth, Michal, primary, Topper, Michael, primary, Iacolina, Michelle D., primary, Walker, Jason M., primary, Forest, Amelie, primary, Shen, Yang, primary, Novosiadly, Ruslan D., primary, and Ferguson, Kathryn M., primary

Published
2023
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8. Supplementary Materials and Methods from Characterization of 7A5: A Human CD137 (4-1BB) Receptor Binding Monoclonal Antibody with Differential Agonist Properties That Promotes Antitumor Immunity

Author

Kotanides, Helen, primary, Sattler, Rose Marie, primary, Lebron, Maria B., primary, Carpenito, Carmine, primary, Shen, Juqun, primary, Li, Jingxing, primary, Surguladze, David, primary, Haidar, Jaafar N., primary, Burns, Colleen, primary, Shen, Leyi, primary, Inigo, Ivan, primary, Pennello, Anthony L., primary, Forest, Amelie, primary, Chen, Xinlei, primary, Chin, Darin, primary, Sonyi, Andreas, primary, Topper, Michael, primary, Boucher, Lauren, primary, Sharma, Prachi, primary, Zhang, Yiwei, primary, Burtrum, Douglas, primary, Novosiadly, Ruslan D., primary, Ludwig, Dale L., primary, Plowman, Gregory D., primary, and Kalos, Michael, primary

Published
2023
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10. Correction to: Discovery and preclinical characterization of the antagonist anti-PD-L1 monoclonal antibody LY3300054

Author

Li, Yiwen, Carpenito, Carmine, Wang, George, Surguladze, David, Forest, Amelie, Malabunga, Maria, Murphy, Mary, Zhang, Yiwei, Sonyi, Andreas, Chin, Darin, Burtrum, Douglas, Inigo, Ivan, Pennello, Anthony, Shen, Leyi, Malherbe, Laurent, Chen, Xinlei, Hall, Gerald, Haidar, Jaafar N., Ludwig, Dale L., Novosiadly, Ruslan D., and Kalos, Michael

Published
2018
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12. Therapeutic high affinity T cell receptor targeting a KRASG12D cancer neoantigen.

Author

Poole, Andrew, Karuppiah, Vijaykumar, Hartt, Annabelle, Haidar, Jaafar N., Moureau, Sylvie, Dobrzycki, Tomasz, Hayes, Conor, Rowley, Christopher, Dias, Jorge, Harper, Stephen, Barnbrook, Keir, Hock, Miriam, Coles, Charlotte, Yang, Wei, Aleksic, Milos, Lin, Aimee Bence, Robinson, Ross, Dukes, Joe D., Liddy, Nathaniel, and Van der Kamp, Marc

Subjects
T cell receptors, MOLECULAR dynamics, SOMATIC mutation, BISPECIFIC antibodies, PEPTIDES, CARCINOGENESIS
Abstract

Neoantigens derived from somatic mutations are specific to cancer cells and are ideal targets for cancer immunotherapy. KRAS is the most frequently mutated oncogene and drives the pathogenesis of several cancers. Here we show the identification and development of an affinity-enhanced T cell receptor (TCR) that recognizes a peptide derived from the most common KRAS mutant, KRASG12D, presented in the context of HLA-A*11:01. The affinity of the engineered TCR is increased by over one million-fold yet fully able to distinguish KRASG12D over KRASWT. While crystal structures reveal few discernible differences in TCR interactions with KRASWT versus KRASG12D, thermodynamic analysis and molecular dynamics simulations reveal that TCR specificity is driven by differences in indirect electrostatic interactions. The affinity enhanced TCR, fused to a humanized anti-CD3 scFv, enables selective killing of cancer cells expressing KRASG12D. Our work thus reveals a molecular mechanism that drives TCR selectivity and describes a soluble bispecific molecule with therapeutic potential against cancers harboring a common shared neoantigen. Cancers often harbor mutations in genes encoding important regulatory proteins, but therapeutic targeting of these molecules proves difficult due to their high structural similarity to their non-mutated counterpart. Here authors show the engineering of T cell engaging bispecific protein able to selectively target cancer cells with a high-frequency mutation in the KRAS oncogene. [ABSTRACT FROM AUTHOR]

Published
2022
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13. Identification and analysis of functional elements in 1% of the human genome by the ENCODE pilot project

Author

Birney, Ewan, Stamatoyannopoulos, John A., Dutta, Anindya, Guigo, Roderic, Gingeras, Thomas R., Margulies, Elliott H., Weng, Zhiping, Snyder, Michael, Dermitzakis, Emmanouil T., Thurman, Robert E., Kuehn, Michael S., Taylor, Christopher M., Neph, Shane, Koch, Christoph M., Asthana, Saurabh, Malhotra, Ankit, Adzhubei, Ivan, Greenbaum, Jason A., Andrews, Robert M., Flicek, Paul, Boyle, Patrick J., Cao, Hua, Carter, Nigel P., Clelland, Gayle K., Davis, Sean, Day, Nathan, Dhami, Pawandeep, Dillon, Shane C., Dorschner, Michael O., Fiegler, Heike, Giresi, Paul G., Goldy, Jeff, Hawrylycz, Michael, Haydock, Andrew, Humbert, Richard, James, Keith D., Johnson, Brett E., Johnson, Ericka M., Frum, Tristan T., Rosenzweig, Elizabeth R., Karnani, Neerja, Lee, Kirsten, Lefebvre, Gregory C., Navas, Patrick A., Neri, Fidencio, Parker, Stephen C. J., Sabo, Peter J., Sandstrom, Richard, Shafer, Anthony, Vetrie, David, Weaver, Molly, Wilcox, Sarah, Yu1, Man, Collins, Francis S., Dekker, Job, Lieb, Jason D., Tullius, Thomas D., Crawford, Gregory E., Sunyaev, Shamil, Noble, William S., Dunham, Ian, Denoeud, France, Reymond, Alexandre, Kapranov, Philipp, Rozowsky, Joel, Zheng, Deyou, Castelo, Robert, Frankish, Adam, Harrow, Jennifer, Ghosh, Srinka, Sandelin, Albin, Hofacker, Ivo L., Baertsch, Robert, Keefe, Damian, Dike, Sujit, Cheng, Jill, Hirsch, Heather A., Sekinger, Edward A., Lagarde, Julien, Abril, Josep F., Shahab, Atif, Flamm, Christoph, Fried, Claudia, Hackermuller, Jorg, Hertel, Jana, Lindemeyer, Manja, Missal, Kristin, Tanzer, Andrea, Washietl, Stefan, Korbel, Jan, Emanuelsson, Olof, Pedersen, Jakob S., Holroyd, Nancy, Taylor, Ruth, Swarbreck, David, Matthews, Nicholas, Dickson, Mark C., Thomas, Daryl J., Weirauch, Matthew T., Gilbert, James, Drenkow, Jorg, Bell, Ian, Zhao, XiaoDong, Srinivasan, K.G., Sung, Wing-Kin, Ooi, Hong Sain, Chiu, Kuo Ping, Foissac, Sylvain, Alioto, Tyler, Brent, Michael, Pachter, Lior, Tress, Michael L., Valencia, Alfonso, Choo, Siew Woh, Choo, Chiou Yu, Ucla, Catherine, Manzano, Caroline, Wyss, Carine, Cheung, Evelyn, Clark, Taane G., Brown, James B., Ganesh, Madhavan, Patel, Sandeep, Tammana, Hari, Chrast, Jacqueline, Henrichsen, Charlotte N., Kai, Chikatoshi, Kawai, Jun, Nagalakshmi, Ugrappa, Wu, Jiaqian, Lian, Zheng, Lian, Jin, Newburger, Peter, Zhang, Xueqing, Bickel, Peter, Mattick, John S., Carninci, Piero, Hayashizaki, Yoshihide, Weissman, Sherman, Hubbard, Tim, Myers, Richard M., Rogers, Jane, Stadler, Peter F., Lowe, Todd M., Wei, Chia-Lin, Ruan, Yijun, Struhl, Kevin, Gerstein, Mark, Antonarakis, Stylianos E., Fu, Yutao, Green, Eric D., Karaoz, Ulaş, Siepel, Adam, Taylor, James, Liefer, Laura A., Wetterstrand, Kris A., Good, Peter J., Feingold, Elise A., Guyer, Mark S., Cooper, Gregory M., Asimenos, George, Dewey, Colin N., Hou, Minmei, Nikolaev, Sergey, Montoya-Burgos, Juan I., Loytynoja, Ari, Whelan, Simon, Pardi, Fabio, Massingham, Tim, Huang, Haiyan, Zhang, Nancy R., Holmes, Ian, Mullikin, James C., Ureta-Vidal, Abel, Paten, Benedict, Seringhaus, Michael, Church, Deanna, Rosenbloom, Kate, Kent, W. James, Stone, Eric A., Batzoglou, Serafim, Goldman, Nick, Hardison, Ross C., Haussler, David, Miller, Webb, Sidow, Arend, Trinklein, Nathan D., Zhang, Zhengdong D., Barrera, Leah, Stuart, Rhona, King, David C., Ameur, Adam, Enroth, Stefan, Bieda, Mark C., Kim, Jonghwan, Bhinge, Akshay A., Jiang, Nan, Liu, Jun, Yao, Fei, Vega, Vinsensius B., Lee, Charlie W.H., Ng, Patrick, Yang, Annie, Moqtaderi, Zarmik, Zhu, Zhou, Xu, Xiaoqin, Squazzo, Sharon, Oberley, Matthew J., Inman, David, Singer, Michael A., Richmond, Todd A., Munn, Kyle J., Rada-Iglesias, Alvaro, Wallerman, Ola, Komorowski, Jan, Fowler, Joanna C., Couttet, Phillippe, Bruce, Alexander W., Dovey, Oliver M., Ellis, Peter D., Langford, Cordelia F., Nix, David A., Euskirchen, Ghia, Hartman, Stephen, Urban, Alexander E., Kraus, Peter, Van Calcar, Sara, Heintzman, Nate, Hoon Kim, Tae, Wang, Kun, Qu, Chunxu, Hon, Gary, Luna, Rosa, Glass, Christopher K., Rosenfeld, M. Geoff, Aldred, Shelley Force, Cooper, Sara J., Halees, Anason, Lin, Jane M., Shulha, Hennady P., Zhang, Xiaoling, Xu, Mousheng, Haidar, Jaafar N. S., Yu, Yong, Birney*, Ewan, Iyer, Vishwanath R., Green, Roland D., Wadelius, Claes, Farnham, Peggy J., Ren, Bing, Harte, Rachel A., Hinrichs, Angie S., Trumbower, Heather, Clawson, Hiram, Hillman-Jackson, Jennifer, Zweig, Ann S., Smith, Kayla, Thakkapallayil, Archana, Barber, Galt, Kuhn, Robert M., Karolchik, Donna, Armengol, Lluis, Bird, Christine P., de Bakker, Paul I. W., Kern, Andrew D., Lopez-Bigas, Nuria, Martin, Joel D., Stranger, Barbara E., Woodroffe, Abigail, Davydov, Eugene, Dimas, Antigone, Eyras, Eduardo, Hallgrimsdottir, Ingileif B., Huppert, Julian, Zody, Michael C., Abecasis, Goncalo R., Estivill, Xavier, Bouffard, Gerard G., Guan, Xiaobin, Hansen, Nancy F., Idol, Jacquelyn R., Maduro, Valerie V.B., Maskeri, Baishali, McDowell, Jennifer C., Park, Morgan, Thomas, Pamela J., Young, Alice C., Blakesley, Robert W., Baylor College of Medicine, Human Genome Sequencing Center, Muzny, Donna M., Sodergren, Erica, Wheeler, David A., Worley, Kim C., Jiang, Huaiyang, Weinstock, George M., Gibbs, Richard A., Graves, Tina, Fulton, Robert, Mardis, Elaine R., Wilson, Richard K., Clamp, Michele, Cuff, James, Gnerre, Sante, Jaffe, David B., Chang, Jean L., Lindblad-Toh, Kerstin, Lander, Eric S., Koriabine, Maxim, Nefedov, Mikhail, Osoegawa, Kazutoyo, Yoshinaga, Yuko, Zhu, Baoli, and de Jong, Pieter J.

Subjects
Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

Author(s): The ENCODE Project Consortium; Analysis Coordination; Ewan Birney (corresponding author) [1]; John A. Stamatoyannopoulos (corresponding author) [2]; Anindya Dutta (corresponding author) [3]; Roderic Guigó (corresponding author) [4, 5]; Thomas [...]

Published
2007
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14. Bispecific Targeting of PD-1 and PD-L1 Enhances T-cell Activation and Antitumor Immunity

Author

Kotanides, Helen, primary, Li, Yiwen, additional, Malabunga, Maria, additional, Carpenito, Carmine, additional, Eastman, Scott W., additional, Shen, Yang, additional, Wang, George, additional, Inigo, Ivan, additional, Surguladze, David, additional, Pennello, Anthony L., additional, Persaud, Krishnadatt, additional, Hindi, Sagit, additional, Topper, Michael, additional, Chen, Xinlei, additional, Zhang, Yiwei, additional, Bulaon, Danielle K., additional, Bailey, Tim, additional, Lao, Yanbin, additional, Han, Bing, additional, Torgerson, Stacy, additional, Chin, Darin, additional, Sonyi, Andreas, additional, Haidar, Jaafar N., additional, Novosiadly, Ruslan D., additional, Moxham, Christopher M., additional, Plowman, Gregory D., additional, Ludwig, Dale L., additional, and Kalos, Michael, additional

Published
2020
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15. Characterization of 7A5: A Human CD137 (4-1BB) Receptor Binding Monoclonal Antibody with Differential Agonist Properties That Promotes Antitumor Immunity

Author

Kotanides, Helen, primary, Sattler, Rose Marie, additional, Lebron, Maria B., additional, Carpenito, Carmine, additional, Shen, Juqun, additional, Li, Jingxing, additional, Surguladze, David, additional, Haidar, Jaafar N., additional, Burns, Colleen, additional, Shen, Leyi, additional, Inigo, Ivan, additional, Pennello, Anthony L., additional, Forest, Amelie, additional, Chen, Xinlei, additional, Chin, Darin, additional, Sonyi, Andreas, additional, Topper, Michael, additional, Boucher, Lauren, additional, Sharma, Prachi, additional, Zhang, Yiwei, additional, Burtrum, Douglas, additional, Novosiadly, Ruslan D., additional, Ludwig, Dale L., additional, Plowman, Gregory D., additional, and Kalos, Michael, additional

Published
2020
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19. Abstract 2730: Preclinical characterization of the anti-PD-L1 monoclonal antibody LY3300054

Author

Carpenito, Carmine, primary, Li, Yiwen, additional, Wang, George X., additional, Malabunga, Maria S., additional, Haidar, Jaafar N., additional, Forest, Amelie, additional, Murphy, Mary Y., additional, Hall, Gerald E., additional, Wang, Cindy, additional, Shen, Leyi, additional, Sonyi, Andreas, additional, Chin, Darin, additional, Pennello, Anthony L., additional, Inigo, Ivan V., additional, Surguladze, David, additional, Yao, Yung-mae, additional, Burtrum, Douglas, additional, Novosiadly, Ruslan D., additional, Persaud, Kris, additional, Ludwig, Dale L., additional, and Kalos, Michael D., additional

Published
2018
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21. Combinations of affinity-enhancing mutations in a T cell receptor reveal highly nonadditive effects within and between complementarity determining regions and chains

Author

Pierce, Brian C., Haidar, Jaafar N., Yong Yu, and Zhiping Weng

Subjects
Gene mutations -- Analysis, Protein binding -- Analysis, Antigen receptors, T cell -- Research, T cells -- Receptors, T cells -- Research, Biological sciences, Chemistry
Abstract

The cooperativity of combinations of point mutations of a T cell receptor (TCR) that binds in vivo to HLA-A2 MHC and a viral peptide is examined. The results have shown the complex nature of TCR association and binding and the structural modeling of anticooperative mutants has determined that side chain clash between proximal mutants have led to nonadditive binding energies.

Published
2010

22. Combinations of Affinity-Enhancing Mutations in a T Cell Receptor Reveal Highly Nonadditive Effects within and between CDRs and Chains

Author

Pierce, Brian G., Haidar, Jaafar N., Yu, Yong, and Weng, Zhiping

Subjects
Models, Molecular, Human T-lymphotropic virus 1, Protein Conformation, Receptors, Antigen, T-Cell, alpha-beta, Receptors, Antigen, T-Cell, Gene Expression, Article, Kinetics, HLA-A2 Antigen, Escherichia coli, Humans, Point Mutation, Oligopeptides, Protein Binding
Abstract

Understanding the energetic and structural response to multiple mutations in a protein-protein interface is a key aspect of rational protein design. Here we investigate the cooperativity of combinations of point mutations of a T cell receptor (TCR) that binds in vivo to HLA-A2 MHC and a viral peptide. The mutations were obtained from two sources: a structure-based design study on the TCR alpha chain (nine mutations) and an in vitro selection study on the TCR beta chain (four mutations). In addition to combining the highest-affinity variants from each chain, we tested other combinations of mutations within and among the chains, for a total of 23 TCR mutants that we measured for binding kinetics to the peptide and major histocompatibility complex. A wide range of binding affinities was observed, from 2- to 1000-fold binding improvement versus that of the wild type, with significant nonadditive effects observed within and between TCR chains. This included an amino acid-dependent cooperative interaction between CDR1 and CDR3 residues that are separated by more than 9 A in the wild-type complex. When analyzing the kinetics of the mutations, we found that the association rates were primarily responsible for the cooperativity, while the dissociation rates were responsible for the anticooperativity (less-than-additive energetics). On the basis of structural modeling of anticooperative mutants, we determined that side chain clash between proximal mutants likely led to nonadditive binding energies. These results highlight the complex nature of TCR association and binding and will be informative in future design efforts that combine multiple mutant residues.

Published
2010

28. A universal combinatorial design of antibody framework to graft distinct CDR sequences: A bioinformatics approach.

Author

Haidar, Jaafar N., Yuan, Qing-An, Zeng, Lin, Snavely, Mark, Luna, Xenia, Zhang, Haifan, Zhu, Wei, Ludwig, Dale L., and Zhu, Zhenping

Abstract

Antibody (Ab) humanization is crucial to generate clinically relevant biologics from hybridoma-derived monoclonal antibodies (mAbs). In this study, we integrated antibody structural information from the Protein Data Bank with known back-to-mouse mutational data to build a universal consensus of framework positions (10 heavy and 7 light) critical for the preservation of the functional conformation of the Complimentarity Determining Region of antibodies. On the basis of FR consensus, we describe here a universal combinatorial library suitable for humanizing exogenous antibodies by CDR-grafting. The six CDRs of the murine anti-human EGFR Fab M225 were grafted onto a distinct (low FR sequence similarity to M225) human FR sequence that incorporates at the 17 FR consensus positions the permutations of the naturally observed amino acid diversities. Ten clones were selected from the combinatorial library expressing phage-displayed humanized M225 Fabs. Surprisingly, 2 of the 10 clones were found to bind EGFR with stronger affinity than M225. Cell-based assays demonstrated that the 10 selected clones retained epitope specificity by blocking EGFR phosphorylation and thus hindering cellular proliferation. Our results suggest that there is a universal and structurally rigid near-CDR set of FR positions that cooperatively support the binding conformation of CDRs. Proteins 2011. © 2012 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Published
2012
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