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(12) Patent Application Publication (10) Pub. No.: US 2012/0164068 A1 Hudson Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2012/0164068 A1 Hudson Et Al US 2012O164068A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2012/0164068 A1 Hudson et al. (43) Pub. Date: Jun. 28, 2012 (54) MMUNO-CONUGATES AND METHODS Publication Classification FOR PRODUCING THEM (51) Int. Cl. A 6LX 39/395 (2006.01) Inventors: Peter John Hudson, Blackburn CI2N 5/3 (2006.01) (76) CI2N 15/63 (2006.01) (AU); Paul Robert Sanders, CI2P 2L/00 (2006.01) Moonee Ponds (AU); Debra CI2N 5/071 (2010.01) Tamvakis, Camberwell (AU); A6II 5L/It (2006.01) Fabio Turatti, Docklands (AU); C07K I6/46 (2006.01) Michael Paul Wheatcroft, CI2N 5/62 (2006.01) Southbank (AU); David Leong, CI2N 5/10 (2006.01) Preston (AU) A6IP35/00 (2006.01) CI2N I/2 (2006.01) CI2N I/19 (2006.01) (21) Appl. No.: 13/383,578 C07K 6/00 (2006.01) A61R 49/00 (2006.01) PCT Fled: Jul. 2, 2010 (52) U.S. Cl. .................. 424/1.49; 530/387.1; 424/130.1; (22) 536/23.53; 435/320.1; 435/69.6; 435/375; 424/9.1:530/387.3; 424/133.1536/23.4: (86) PCT NO.: PCT/AU2O1 O/OOO847 435/328; 435/252.3:435/252.33:435/252.31; 435/252.34; 435/252.35:435/326; 435/254.23; S371 (c)(1), 435/254.21 (2), (4) Date: Mar. 16, 2012 (57) ABSTRACT The present invention provides an isolated protein compris Related U.S. Application Data ing an immunoglobulin variable region comprising at least two cysteine residues positioned within framework region 1 (60) Provisional application No. 61/223,353, filed on Jul. 6, such that if at least two of the cysteine residues are not 2009, provisional application No. 61/256,703, filed on conjugated to another compound a disulphide bond forms Oct. 30, 2009. between the cysteine residues. Preferably the protein com prises an immunoglobulin heavy chain variable region and an immunoglobulin light chain variable region, wherein at least one of the variable regions comprises the two cysteine resi (30) Foreign Application Priority Data dues. The present invention also provides a protein that binds to TAG72. The present invention also provides conjugates of Jul. 3, 2009 (AU) ................................ 20099.03127 the protein and another compound. Patent Application Publication Jun. 28, 2012 Sheet 1 of 52 US 2012/O164068 A1 i. Patent Application Publication Jun. 28, 2012 Sheet 2 of 52 US 2012/O164068 A1 E. Patent Application Publication Jun. 28, 2012 Sheet 3 of 52 US 2012/O164068 A1 s i i Patent Application Publication Jun. 28, 2012 Sheet 4 of 52 US 2012/O164068 A1 i Patent Application Publication Jun. 28, 2012 Sheet 5 of 52 US 2012/O164068 A1 Patent Application Publication Jun. 28, 2012 Sheet 6 of 52 US 2012/O164068 A1 a resisiae ass. & 8 3:...' ig:rk & Patent Application Publication Jun. 28, 2012 Sheet 7 of 52 US 2012/O164068 A1 i Patent Application Publication Jun. 28, 2012 Sheet 8 of 52 US 2012/O164068 A1 Patent Application Publication Jun. 28, 2012 Sheet 9 of 52 US 2012/O164068 A1 Patent Application Publication Jun. 28, 2012 Sheet 10 of 52 US 2012/O164068 A1 ir-stated FR w1 H13-H16 jr-rritated FR: 7- 4-7 Figure 7B Patent Application Publication Jun. 28, 2012 Sheet 11 of 52 US 2012/O164068 A1 888: 8& Patent Application Publication Jun. 28, 2012 Sheet 12 of 52 US 2012/O164068 A1 ************************* 88:88:8: , ix: igare: Patent Application Publication Jun. 28, 2012 Sheet 13 of 52 US 2012/O164068 A1 Exckstratic 8 & &: 8: 8: 8: : 8: 88: 8: 38 88 (Xixx Patent Application Publication Jun. 28, 2012 Sheet 14 of 52 US 2012/O164068 A1 oord os? by? oz? gotaanã, Patent Application Publication Jun. 28, 2012 Sheet 15 of 52 US 2012/O164068 A1 Patent Application Publication Jun. 28, 2012 Sheet 16 of 52 US 2012/O164068 A1 Patent Application Publication Jun. 28, 2012 Sheet 17 of 52 US 2012/O164068 A1 Patent Application Publication Jun. 28, 2012 Sheet 22 of 52 US 2012/O164068 A1 88.3:38 3. : &&&&&&&&& : 88: 88 38 8 ×3×3×3×3&&3&??&*& * ** * ? «;& * * & & 8 & ----------******************* 8::::::::: 88: 88:::::::: Patent Application Publication Jun. 28, 2012 Sheet 23 of 52 US 2012/O164068 A1 8,833.83 8::::::::::: 3:8:88:8::::::::::x:y & - 8 8 38 & 88:88: 3888: *igi & 32 Patent Application Publication Jun. 28, 2012 Sheet 24 of 52 US 2012/O164068 A1 Ápoq?AVp?XeN ÁÐEd—> auen 8/9?7ZI Patent Application Publication Jun. 28, 2012 Sheet 25 of 52 US 2012/O164068 A1 es "es O b k t B Ch. 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Costigate 3 xiiaxxy °C. cxx88 x-axxy 8834 (Exigex s x 38 irre irs igrate 24 Patent Application Publication Jun. 28, 2012 Sheet 47 of 52 US 2012/O164068 A1 & x^-*.^e----- * 8 : 88x3-8-3-83-8: 3. 8:8:8: 8, ::::::::: 3. 8: 8. & XXXs 8 88-888-8-8-8 Patent Application Publication Jun. 28, 2012 Sheet 48 of 52 US 2012/O164068 A1 Figure 26A Patent Application Publication Jun. 28, 2012 Sheet 49 of 52 US 2012/O164068 A1 Figure 26B Patent Application Publication Jun. 28, 2012 Sheet 50 of 52 US 2012/O164068 A1 so so « Catax. Figure 26C Patent Application Publication Jun. 28, 2012 Sheet 51 of 52 US 2012/O164068 A1 8 ed Patent Application Publication Jun. 28, 2012 Sheet 52 of 52 US 2012/O164068 A1 Figure 27A Figure 278 Figure 27C US 2012/0164068 A1 Jun. 28, 2012 IMMUNO-CONUGATES AND METHODS various conjugate species within the heterogeneous mixture FOR PRODUCING THEM resulting from a conjugation reaction. 0005. Furthermore, non-specific conjugation of a com CROSS-REFERENCE TO RELATED pound to an antibody or protein comprising an antigen bind APPLICATIONS ingdomain thereofmay reduce or completely prevent binding of the antibody/protein to an antigen, for example, if the 0001. This application claims priority from Australian compound is conjugated to a region required for antigen Patent Application No. 2009903127 entitled “Immuno-con binding. This risk is increased in proteins that comprise anti jugates and methods for producing them filed on 3 Jul. 2009: gen binding domains that are far Smaller than an intact anti U.S. Patent Application No. 61/223,353 entitled “Immuno body in which there may be few residues suitable for conju conjugates and methods for producing them filed on 6 Jul. gation that are not important for antigen binding. For 2009; and U.S. Patent Application No. 61/256,703 entitled example, proteins comprising little more than antigenbinding 'Variable domain molecules and methods of use filed on 30 domains of an antibody have few sites to which a compound Oct. 2009, the entire contents of which are incorporated by can be conjugated without reducing or preventing antigen reference.
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