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(12) Patent Application Publication (10) Pub. No.: US 2016/0033516 A1 Hunter Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2016/0033516 A1 Hunter Et Al US 2016.0033516A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2016/0033516 A1 Hunter et al. (43) Pub. Date: Feb. 4, 2016 (54) USE OF POLYCLONAL AND MONOCLONAL Publication Classification ANTIBODES SPECIFICFOR 3-PHOSPHOHISTONE (51) Int. Cl. GOIN33/574 (2006.01) (71) Applicant: SALK INSTITUTE FOR GOIN33/68 (2006.01) BIOLOGICAL STUDIES, La Jolla, CA GOIN 33/573 (2006.01) (US) (52) U.S. C. CPC ........ G0IN33/57496 (2013.01); G0IN33/573 (72) Inventors: Tony Hunter, Del Mar, CA (US); (2013.01); G0IN33/6854 (2013.01); G0IN Stephen Rush Fuhs, San Diego, CA 2800/52 (2013.01) (US); Jill Meisenhelder, Vista, CA (US) (57) ABSTRACT (73) Assignee: SALKINSTITUTE FOR Isolated monoclonal antibodies and antigen binding frag BIOLOGICAL STUDIES, La Jolla, CA ments are disclosed herein that specifically bind polypeptides (US) comprising a histidine phosphorylated at N3 (3-pHis). Nucleic acids encoding these antibodies, vectors including (21) Appl. No.: 14/789,811 these nucleic acids, and host cells transformed with these vectors and nucleic acids are also disclosed. Methods are also Filed: Jul. 1, 2015 disclosed for using these antibodies, such as for detection of (22) polypeptides comprising a histidine phosphorylated at N3 (3-pHis), detection of a tumor, monitoring the effectiveness Related U.S. Application Data of therapeutic agent, and identifying antibiotics. In some (60) Provisional application No. 62/031,796, filed on Jul. embodiments, the methods can be used to investigate signal 31, 2014. transduction pathways. Patent Application Publication Feb. 4, 2016 Sheet 1 of 16 US 2016/0033516 A1 FG. A histidine Q NH HO O NH re N N O NH Ns-NH HO HO HO NN/ bH N 1-phosphohistidine OS-7 N / (1-phis) HO OH 3-phosphohistidine (3-pHis) G. 3 us s E ill-illy s s N NH, { 8 E3 : C Y- & 8 $3 ristidine : 3: "y N s s N s ''N: 88. C. : C & O Y- C & ; : 85. r&b. t -piza Y : 38: Patent Application Publication Feb. 4, 2016 Sheet 2 of 16 US 2016/0033516 A1 x x 8 & 8 & x wo i six. - s * sea s: ass ta i e ses s Ace s ne xx : Patent Application Publication Feb. 4, 2016 Sheet 3 of 16 US 2016/0033516 A1 Áueuq?ap?dadezLd-g Patent Application Publication Feb. 4, 2016 Sheet 4 of 16 US 2016/0033516 A1 eft s to 2 5 FIG. 2A 3-piza" : Anti-3-phis '' (antisera) his pSyr FIG. 2B SA, F.G. 2C FIG. 2F is: of a SS-PSA. : : - ; ; ; ; ; ; ; i. SOC 88 58 2,3-DPG (NA) - 1 18 OG 1k - ; 3. 108 k ad SSC - -, -, -, -, - - - - - kOa: pHis (7303) PGA (ng). 250 5 10 50 95. GS-PGA F.G. 2G 3. 18; 3-pHis 7303) (7303-MC39-4) Patent Application Publication Feb. 4, 2016 Sheet 5 of 16 US 2016/0033516 A1 FIG. 3B (cotassie 33 FIG. 3C N888 its s 233 s 230 s 238 s 300 S200 S. 38 S. 233 S 2 S. S. kia SS Anti-t-phis 28 & antisera FIG. 3D BesS Cootassié 39 g3 & is is .3 is cc E3 ES S. S. 8 SF 8: ES S3; S. E32 FG.3E PGA88 ing 5 233 s 280 S 200 is 23 S 3 S 2O3 k3& Anti-3-phis 37 25: : 33:saga E3 Patent Application Publication Feb. 4, 2016 Sheet 6 of 16 US 2016/0033516 A1 F.G. 4B Airsity-purified FAas Erotein-A purified p3s &As asyks: 3-pits 3S &uÉticial 3-pés Aas Patent Application Publication Feb. 4, 2016 Sheet 7 of 16 US 2016/0033516 A1 FIG 5A sic 3S sic aSC rsrc aSC SSC - - - - si. i8 issyr F.G. 5B Pancreaticw cancer ceiliness FIG.SC A-K-3 8:AeCa2 Casai : Kp4 -3:23:8 as:c- SS. - . ACY SCS 8: 1-phiis (Aix SC 1-3 is 3 is {At SC44-33 Patent Application Publication Feb. 4, 2016 Sheet 8 of 16 US 2016/0033516 A1 F.G. 6A 3.88.3S F-88-238 o: F.G. 6B F.G. 6G F.G. 6D FIG. 6G Patent Application Publication Feb. 4, 2016 Sheet 9 of 16 US 2016/0033516 A1 F.G. 7A - 70.80: N iii.pH.G.S D S VESA.E.K 8. 3. s: w &r 3. 8.: ax - :s : 8. : 3 : S. s |--|--|--|3. |-as 3.i rt--3. ^ 9:0 0. :00 200 300 pH.GESAWNENR w X w. 50- s: 40: 8 3C: aa. : 20 . E. s 10: X s: k x, w s C-: ld, all - ill, IllLt. i.li hill 1, 2 33 43 50 Patent Application Publication Feb. 4, 2016 Sheet 10 of 16 US 2016/0033516 A1 680S V8"ROHH Patent Application Publication Feb. 4, 2016 Sheet 13 of 16 US 2016/0033516 A1 G. A. G. s :::::::::::: 388& F. E. Patent Application Publication Feb. 4, 2016 Sheet 14 of 16 US 2016/0033516 A1 F. : Fi. F. : G. K. Patent Application Publication Feb. 4, 2016 Sheet 15 of 16 US 2016/0033516 A1 F. A 8, 23. F:, 28 F. : FG, E. F. E. FG, 2. six F, 2 F. Patent Application Publication Feb. 4, 2016 Sheet 16 of 16 US 2016/0033516 A1 F. 2. FG. F. F. F. G. ass G. 8 & 3.X& FG, F. F. US 2016/0033516 A1 Feb. 4, 2016 USE OF POLYCLONAL AND MONOCLONAL acids 32, 145 (January, 2007); McAllister et al., Biochemical ANTIBODIES SPECIFC FOR Society transactions 41, 1072 (August, 2013)). NME1 and 3-PHOSPHOHISTONE the closely related NME2 catalyze transfer of phosphate from ATP onto NDPs through a 1-pHis enzyme intermediate. The CROSS REFERENCE TO RELATED 3-pHis isomer has been shown to be more thermodynamically APPLICATIONS stable (Attwood et al., Amino acids 32, 145 (January, 2007)) than 1-pHis and may be more prevalent. 3-pHis is used by 0001. This claims the benefit of U.S. Application No. bacterial histidine kinases that autophosphorylate to initiate 62/031,796, filed Jul. 31, 2014, which is incorporated by phosphotransfer cascades and it also plays an important role reference herein. as an enzymatic intermediate for phospholipase D as well as ACKNOWLEDGMENT OF GOVERNMENT several key metabolic enzymes including; phosphoglycerate SUPPORT mutase (PGAM), succinyl-CoA synthetase (SCS), ATP-cit rate lyase (ACLY) (see, for example, Bond et al., J. Biol. 0002 This invention was made with government support Chem. 276, 3247 (2001)). under grant no. 5 RO 1 CA082683-15 awarded by the 0006. There is a need for the development of specific, National Institutes of Health and grant no.5 T32 CA009370 monoclonal antibodies (mAbs) for detection of pHis that can 31 from the National Institutes of Health. The government has be used to detect and functionally evaluate novel sites of certain rights in the invention. protein phosphorylation. These antibodies can be used, for example, to investigate signal transduction pathways. FIELD 0003. This relates to the field of antibodies, specifically to SUMMARY the use of antibodies that specifically bind a polypeptide that 0007 Uses of monoclonal antibodies, as well as antigen includes a histidine phosphorylated at N3 (3-pHis), such as binding fragments thereof, are disclosed herein that specifi for the identification of antibiotics and detecting the presence cally bind polypeptides including a histidine phosphorylated of a tumor in a Subject. at N3 (3-pHis). In some embodiments, the antibody includes a heavy chain variable region and a light chain variable BACKGROUND region, wherein the heavy chain variable region comprises a 0004. The majority of intracellular proteins are phospho H-CDR1, a H-CDR2, and a H-CDR3, wherein the antibody rylated at any given time, and, while nine of the 20 amino or antigenbinding fragment includes one of: a) the H-CDR1, acids can be phosphorylated, the current focus has been on the H-CDR2, and the H-CDR3 of the heavy chain variable serine (Ser), threonine (Thr), and tyrosine (Tyr) phosphory region of the amino acid sequence set forth as SEQID NO: 1; lation despite pHis having been first identified over 50 years b) the H-CDR1, the H-CDR2, and the H-CDR3 of the heavy ago (Boyer, J. Biol. Chem., 3306 (1962)). These OH-contain chain variable region of the amino acid sequence set forth as ing amino acids form acid-stable, phosphoester (P -O) SEQ ID NO: 2; c) the H-CDR1, the H-CDR2, and the bonds upon phosphorylation (Attwood, et al., Amino acids H-CDR3 of the heavy chain variable region of the amino acid 32, 145 (January, 2007)). Histidine (His) forms a heat and sequence set forth as SEQID NO:3: or d) the H-CDR1, the acid-labile phosphoramidate (P N) bond when phosphory H-CDR2, and the H-CDR3 of the heavy chain variable region lated. Phosphospecific antibodies have enabled the routine of the amino acid sequence set forth as SEQ ID NO: 4, study of phosphoesterprotein phosphorylation, and the use of wherein the monoclonal antibody specifically binds a MS-proteomics has identified over 200,000 non-redundant polypeptide comprising a histidine phosphorylated at N3 sites of phosphorylation (Hornbeck et al., Nucl.acids res 40, (3-pHis). In additional embodiments, the light chain variable D261 (January, 2012)). The lack of specific antibodies to region of the monoclonal antibody or antigen binding frag study pHis and the relative instability of the P N bond under ment includes a L-CDR1, a L-CDR2, and a L-CDR3, wherein typical conditions used for proteomics have made it impos the antibody or antigen binding fragment includes one of: a) sible to determine the prevalence of pHis, although it has been the L-CDR1, the L-CDR2, and the L-CDR3 of the light chain estimated that up to 6% of phosphorylation in eukaryotes variable region of the amino acid sequence set forth as SEQ occurs on His (Matthews, Pharmac.
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