Bispecific antibodies targeting mutant RAS neoantigens.
Jacqueline Douglass,Jacqueline Douglass,Emily Han-Chung Hsiue,Emily Han-Chung Hsiue,Brian J. Mog,Michael S. Hwang,Michael S. Hwang,Sarah R. DiNapoli,Sarah R. DiNapoli,Alexander H. Pearlman,Alexander H. Pearlman,Michelle S. Miller,Michelle S. Miller,Katharine M. Wright,Katharine M. Wright,P. Aitana Azurmendi,P. Aitana Azurmendi,Qing Wang,Qing Wang,Suman Paul,Annika Schaefer,Annika Schaefer,Andrew D. Skora,Andrew D. Skora,Marco Dal Molin,Marco Dal Molin,Maximilian F. Konig,Liu Qiang,Liu Qiang,Evangeline Watson,Evangeline Watson,Yana Li,Michael B. Murphy,Drew M. Pardoll,Chetan Bettegowda,Nickolas Papadopoulos,Sandra B. Gabelli,Kenneth W. Kinzler,Bert Vogelstein,Shibin Zhou +39 more
TLDR
In this article, single-chain variable fragments (scFvs) were used to identify peptides derived from recurrent RAS mutations, G12V and Q61H/L/R, in the context of two common human leukocyte antigen (HLA) alleles.Abstract:
Mutations in the RAS oncogenes occur in multiple cancers, and ways to target these mutations has been the subject of intense research for decades. Most of these efforts are focused on conventional small-molecule drugs rather than antibody-based therapies because the RAS proteins are intracellular. Peptides derived from recurrent RAS mutations, G12V and Q61H/L/R, are presented on cancer cells in the context of two common human leukocyte antigen (HLA) alleles, HLA-A3 and HLA-A1, respectively. Using phage display, we isolated single-chain variable fragments (scFvs) specific for each of these mutant peptide-HLA complexes. The scFvs did not recognize the peptides derived from the wild-type form of RAS proteins or other related peptides. We then sought to develop an immunotherapeutic agent that was capable of killing cells presenting very low levels of these RAS-derived peptide-HLA complexes. Among many variations of bispecific antibodies tested, one particular format, the single-chain diabody (scDb), exhibited superior reactivity to cells expressing low levels of neoantigens. We converted the scFvs to this scDb format and demonstrated that they were capable of inducing T cell activation and killing of target cancer cells expressing endogenous levels of the mutant RAS proteins and cognate HLA alleles. CRISPR-mediated alterations of the HLA and RAS genes provided strong genetic evidence for the specificity of the scDbs. Thus, this approach could be applied to other common oncogenic mutations that are difficult to target by conventional means, allowing for more specific anticancer therapeutics.read more
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Targeting a neoantigen derived from a common TP53 mutation
Emily Han-Chung Hsiue,Emily Han-Chung Hsiue,Katharine M. Wright,Katharine M. Wright,Jacqueline Douglass,Jacqueline Douglass,Michael S. Hwang,Michael S. Hwang,Brian J. Mog,Alexander H. Pearlman,Alexander H. Pearlman,Suman Paul,Sarah R. DiNapoli,Sarah R. DiNapoli,Maximilian F. Konig,Qing Wang,Qing Wang,Annika Schaefer,Annika Schaefer,Michelle S. Miller,Michelle S. Miller,Andrew D. Skora,Andrew D. Skora,P. Aitana Azurmendi,P. Aitana Azurmendi,Michael B. Murphy,Liu Qiang,Liu Qiang,Evangeline Watson,Evangeline Watson,Yana Li,Drew M. Pardoll,Chetan Bettegowda,Nickolas Papadopoulos,Kenneth W. Kinzler,Bert Vogelstein,Sandra B. Gabelli,Shibin Zhou +37 more
TL;DR: In this paper, the authors describe the identification of an antibody highly specific to the most common TP53 mutation (R175H, in which arginine at position 175 is replaced with histidine) in complex with a common human leukocyte antigen-A (HLA-A) allele on the cell surface.
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Neoantigen: A New Breakthrough in Tumor Immunotherapy.
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Emerging new therapeutic antibody derivatives for cancer treatment
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Expanding the Reach of Precision Oncology by Drugging All <i>KRAS</i> Mutants
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Cross-HLA targeting of intracellular oncoproteins with peptide-centric CARs
Mark Yarmarkovich,Quinlen F. Marshall,John M. Warrington,Rasika Premaratne,Alvin Farrel,David Groff,Wei Li,Moreno Di Marco,Erin Runbeck,Hau Truong,Jugmohit S. Toor,Sarvind Tripathi,Son Nguyen,Helena Shen,Tiffany Noel,Nicole L. Church,Amber K. Weiner,Nathan M. Kendsersky,Daniel Martinez,Rebecca Weisberg,Molly Christie,Laurence C. Eisenlohr,Kristopher R. Bosse,Kristopher R. Bosse,Dimiter S. Dimitrov,Stefan Stevanovic,Nikolaos G. Sgourakis,Ben R. Kiefel,John M. Maris,John M. Maris +29 more
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References
More filters
Journal ArticleDOI
Database resources of the National Center for Biotechnology Information
David L. Wheeler,Deanna M. Church,Ron Edgar,Scott Federhen,Wolfgang Helmberg,Thomas L. Madden,Joan Pontius,Gregory D. Schuler,Lynn M. Schriml,Edwin Sequeira,Tugba O. Suzek,Tatiana Tatusova,Lukas Wagner +12 more
TL;DR: In addition to maintaining the GenBank(R) nucleic acid sequence database, the National Center for Biotechnology Information (NCBI) provides data analysis and retrieval resources for the data in GenBank and other biological data made available through NCBI’s website.
Journal ArticleDOI
Cancer Genome Landscapes
Bert Vogelstein,Nickolas Papadopoulos,Victor E. Velculescu,Shibin Zhou,Luis A. Diaz,Kenneth W. Kinzler +5 more
TL;DR: This work has revealed the genomic landscapes of common forms of human cancer, which consists of a small number of “mountains” (genes altered in a high percentage of tumors) and a much larger number of "hills" (Genes altered infrequently).
Journal ArticleDOI
Neoantigens in cancer immunotherapy
TL;DR: Observations indicate that neoantigen load may form a biomarker in cancer immunotherapy and provide an incentive for the development of novel therapeutic approaches that selectively enhance T cell reactivity against this class of antigens.
Journal ArticleDOI
CD-HIT Suite
TL;DR: A new web server, CD-HIT Suite, is developed for clustering a user-uploaded sequence dataset or comparing it to another dataset at different identity levels and users can now interactively explore the clusters within web browsers.
Journal ArticleDOI
A comprehensive survey of Ras mutations in cancer
TL;DR: Examining the mutational spectra of Ras isoforms curated from large-scale tumor profiling found that each isoform exhibits surprisingly distinctive codon mutation and amino-acid substitution biases, which were unexpected given that these mutations occur in regions that share 100% amino- acid sequence identity among the 3 isoforms.
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