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US 2016.0052982A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2016/0052982 A1 Cohen et al. (43) Pub. Date: Feb. 25, 2016 (54) METHODS AND SYSTEMIS FOR DESIGNING Related U.S. Application Data AND/OR CHARACTERIZING SOLUBLE (60) Provisional application No. 61/813,835, filed on Apr. LPIDATED LGAND AGENTS 19, 2013, provisional application No. 61/811.249, filed on Apr. 12, 2013. (71) Applicants: TUFTS MEDICAL CENTER, Boston, Publication Classification MA (US); TRUSTEES OF TUFTS COLLEGE, Medford, MA (US) (51) Int. C. C07K 4/47 (2006.01) (72) Inventors: Charles Cohen, Weston, MA (US); C07K 7/06 (2006.01) Krishna Kumar, Cambridge, MA (US); C07K 7/08 (2006.01) Jamie Raudensky Doyle, Newton, MA GOIN33/50 (2006.01) (52) U.S. C. (US); Alan S. Kopin, Wellesley, MA CPC ........ C07K 14/4703 (2013.01); G0IN33/5023 (US) (2013.01); C07K 7/06 (2013.01); C07K 7/08 (2013.01); A61 K38/00 (2013.01) (21) Appl. No.: 14/783,489 (57) ABSTRACT (22) PCT Fled: Mar. 13, 2014 The present application provides methods for preparing soluble lipidated ligandagents comprising a ligand entity and (86) PCT NO.: PCT/US2O14/026.662 a lipid entity, and in some embodiments, provides relevant parameters of each of these components, thereby enabling S371 (c)(1), appropriate selection of components to assemble active (2) Date: Oct. 9, 2015 agents for any given target of interest. Patent Application Publication Feb. 25, 2016 Sheet 1 of 13 US 2016/0052982 A1 hita CKR wM S-C& 8-5 wn S-88 - Sif the saxes ..? s ligard, log(N) Riotse CXR wha S-C8 &S-Sf e S-882. S. s S. S kg i.ig888 it -S: -: -8 ligard, log} Figure 1 Patent Application Publication Feb. 25, 2016 Sheet 2 of 13 US 2016/0052982 A1 s -- Sssrss SSSSXXX s - C&S 3.5 it. -- ties i-S3. <x -H tGasnin eartfol & 9. &S s s s & ethered ligand chia, gwei) ise (Rt -- Sses i4S, SF - - is 3-SF -- Ssss SS -H tsaari's contro) Tethered ligarst eNA, (ngwell) Figure 2 Patent Application Publication Feb. 25, 2016 Sheet 3 of 13 US 2016/0052982 A1 Hilar Cy Figure 3 Patent Application Publication Feb. 25, 2016 Sheet 4 of 13 US 2016/0052982 A1 s EEs it b s& : 8 3. :8-- - -S&r: ; 3.8 a- as 8& |-- s-chen $48-57 - a f ; : y f is As f S. 3. S. ------ s: - - - r s SEESS, Stylis isse it d sis is: :38 : sS -- 3:38:8 S. X . .. E. e 8& .383. S. -r s s & .. -SS y S Risand, agil ligates, iog{S} W Figure 4 Patent Application Publication Feb. 25, 2016 Sheet S of 13 US 2016/0052982 A1 f : Ef SR 835, s.S. ss. -- -Šays :::::) 's -- S-SES&S&S s : - s s wa . S. ; -S Rigsyst, Rosi) E.issing, logists is is Sists. S. -- Ssix:S$ -- Si-Sia: : Š.issini, Sassists Figure 5 Patent Application Publication Feb. 25, 2016 Sheet 6 of 13 US 2016/0052982 A1 **** ????????????????? zzzzzzzzzz! igure 6 Patent Application Publication Feb. 25, 2016 Sheet 7 of 13 US 2016/0052982 A1 Sechaia sociyi site site isjection 8tec assical hiypersensitivity systic w &R i.e. siegii.3 Citi &idy a -wº·? ise site is extiri Figure 7 Patent Application Publication Feb. 25, 2016 Sheet 8 of 13 US 2016/0052982 A1 A &signia EcKiss ED. GR3}es Peptide linker NC-Myc linker / ligand N N A | NH- Š Š Š-CO H -------N------------> an: -'s - -, -, -o- -N-tw. N ria Pamific Acid linker igand Figure 8 Patent Application Publication Feb. 25, 2016 Sheet 9 of 13 US 2016/0052982 A1 S-S-COOH -P-O-C-F-F-G--- co SPCC s-CCK4-Gly-COOH -N- W ---F-G-COOH O H i-CCK4-Gly-COOH }{s-os-R Y. $4.a. His Molecular Weights (Da) Peptides HPC Purity (%) calculated Observed i-Sub P-COOH" 98 2294.8 2295.1 M+- s-CCK-Gly-COOH 99 S547 655.5 M+H" -CCK-Gly-COOH 98 430.7 1453.3 M+Na" Figure 9 Patent Application Publication Feb. 25, 2016 Sheet 10 of 13 US 2016/0052982 A1 A e sers S$ NK R se 3 i. es S. St a 2 a: s ---- SP-COOH , - ? - S-SP-COOH 2 See a . - se t - s to aer Tethered ligand cMA, gwell) s Peptide, log(N) s NK2R s NK2R e se 40 3. 25. es S 30 is a i 75- - - -SP-COX ss 5 & SubP 3, 20 c. tcCK4 S: , -- S-SP-COOH st SO is "it. is...secs:...:r a -sus. s. 25- xx a 3-re:...r. c s-S-S-S-S-r&33 : -- h O - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - s 3 4. x No ,gand - 2 - O 8 -S ww. ethered ligand cDNA, (ngi wet S Peptide, log(N) C NK3r 4. --- ESP 3. L.: t: t - 2 g-r- ... -Sub-COOH -v- s-SubP-COOH f 25 s Q&:3 ::: i 2 3. No .Egand -12 Tethered Ligand conA, (ngiwell) (Peptide), log(N) MS SMAS Figure 10 Patent Application Publication Feb. 25, 2016 Sheet 11 of 13 US 2016/0052982 A1 A B s NK R NK R or 5. -- SP-COO * S. -- SubF ... s-Sib-COO \ Y. - s s runrST (CP-9999), log(M) CP-93994, log(N) Figure 11 Patent Application Publication Feb. 25, 2016 Sheet 12 of 13 US 2016/0052982 A1 s CCK2R SS. CCK2R S 50 ses 8 t & SS 40 -r-, --- S. f 3 - " 3 i 5 30- / A. to CCK4-Gly c 5 -- {s-w-. -CCK4-Gy-COO-a a ff : 20 s/ Cal Si if eod -- S-CCK4-Gly-COOH f 82 Å. isS. 10i,'-5-3-3-3-3 -- w O- f s X s 2 3. 4. No -2. -i. -3 -6 S. Fethered ligand cENA, (ngwei) s Ligand Peptide, log(N) s CCKR CCK1R 50 se 150 .e AO- ee 125 58s so - CCK4-Gly 3 100- A. CCK4-Gly-COOk r. SubP , -v- s-CCK4-Gly-COOH X 2. 3 ga: 10 i of cle - 4 3. 4. s ethered tigand cinA, Engfweil) is Ligand Peptide, log(M) MT SMA Figure 12 Patent Application Publication Feb. 25, 2016 Sheet 13 of 13 US 2016/0052982 A1 A B CCK2R s CCK2R 50 150 - so S5 40. (...s.1 is e5 12of "e -'N -a- -CCK4-Gly-COOH 3. ... v. -- toCK4-Gly g 90. -v- s-cCK4-Gly-COOH : , 20- ; 803:. “r-5 A. N * , i 10 ti-i-...-E. 5 w: 30- : N O -i. ---...Y.Css. -12 -: -8 -6 NC -12 - -8 - s sitor YMC22, log(M) s inhibitor Y022, log(N) Figure 13 US 2016/0052982 A1 Feb. 25, 2016 METHODS AND SYSTEMIS FOR DESIGNING ing that such system can effectively and reliably permit AND/OR CHARACTERIZING SOLUBLE design, identification, and/or selection of ligand entities and/ LPDATED LGAND AGENTS or lipid entities that, when linked together, form a conjugate that is soluble under relevant physiological conditions. CROSS-REFERENCE TO RELATED 0006. In some embodiments, provided systems for design APPLICATIONS ing, identifying and/or selecting ligand entities and/or lipid 0001. This application claims priority to U.S. provisional entities may include comparison of one or more attributes or patent application Ser. No. 61/811.249, filed Apr. 12, 2013 characteristics of a tethered form of a ligand entity with an and Ser. No. 61/813,835, filed Apr. 19, 2013, the disclosures untethered form of the ligand entity (e.g., an agent consisting of which are hereby incorporated by reference in their of the ligand entity) using one or more in vitro assays. Alter entirety. natively or additionally, in Some embodiments, provided sys tems for designing, identifying and/or selecting ligand enti STATEMENT REGARDING FEDERALLY ties and/or lipid entities may include comparison of one or SPONSORED RESEARCH ORDEVELOPMENT more attributes or characteristics of a tethered form of a ligand entity with an untethered form of the ligand entity 0002 This invention was made with support under Grant (e.g., an agent consisting of the ligand entity) using one or Nos. R01 GMO65500 and R01 CA125033, both awarded by more in Vivo assays. In some embodiments, a desirable lipid the National Institutes of Health (NIH). The government has entity may be one that shows a difference (e.g., a statistically certain rights in the invention. significant difference) in one or more such attributes or char acteristics when in tethered form as compared with unteth BACKGROUND ered form. For example, in some embodiments, a desirable 0003) A significant fraction of effective therapeutic agents lipid entity may show greater affinity for, increased on-rate to, act through interaction with cell Surface receptors or other decreased off-rate from, and/or greater effect on a relevant membrane-associated targets (e.g., ion channels, enzymes, target (e.g., receptor) when utilized in tethered form as com etc). Significant investment has been directed to development pared with untethered form. In some embodiments, differ of additional Such agents. Of particular interest are agents ence may be or include an enhanced beneficial effect. In some susceptible to tissue-specific delivery. embodiments, a difference may be or include a diminished negative effect. SUMMARY 0007. In some embodiments, soluble lipidated ligand 0004. The present invention provides soluble lipidated agents show a solubility under physiologically relevant con ligand agents useful in a variety of diagnostic, therapeutic ditions that is reasonably comparable to that of the unlipi and/or research contexts. In general, provided agents com dated form of the ligand entity.
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