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EP-3129065-B1 - TARGETED DRUG DELIVERY THROUGH AFFINITY BASED LINKERS

EP3129065B1EP 3129065 B1EP3129065 B1EP 3129065B1EP-3129065-B1

Inventors

  • SENGUPTA, SHILADITYA
  • ROY, Monideepa
  • GUPTA, Nimish
  • HOSSAIN, Seikh Samad

Dates

Publication Date
20260513
Application Date
20150311

Claims (19)

  1. A targeted drug delivery conjugate comprising: (i) a targeting ligand, wherein the targeting ligand is an antibody; (ii) an affinity ligand linked to said targeting ligand, wherein the affinity ligand is 4-mercaptoethyl pyridine (4-MEP) or a triazine; and (iii) a therapeutic agent linked to said affinity ligand via a linker; wherein said affinity ligand is covalently connected to said therapeutic agent; and said affinity ligand is non-covalently connected to said targeting ligand.
  2. The targeted drug delivery conjugate of claim 1, wherein the antibody is a monoclonal antibody or polyclonal antibody.
  3. The targeted drug delivery conjugate of claim 1, wherein the targeting ligand binds a protein, receptor, or marker expressed on the surface of a cancer cell.
  4. The targeted drug delivery conjugate of claim 1, wherein the affinity ligand binds with high affinity and/or specificity with the targeting ligand.
  5. The targeted drug delivery conjugate of claim 1, wherein the affinity ligand is a triazine.
  6. The targeted drug delivery conjugate of claim 1, wherein the affinity ligand is 4-mercaptoethyl pyridine.
  7. The targeted drug delivery conjugate of claim 1, wherein the linker is selected from the group consisting of a bond, hydrocarbons, amino acids, peptides, polyethylene glycols, cyclodextrin, and any derivatives and combinations thereof.
  8. The targeted drug delivery conjugate of claim 1, wherein the therapeutic agent is linked to the linker via a non-cleavable linking group or a cleavable linking group.
  9. The targeted drug delivery conjugate of claim 1, wherein the affinity ligand is linked to the linker via a non-cleavable linking group or a cleavable linking group.
  10. The targeted drug delivery conjugate of claim 1, wherein the linker is a branched linker.
  11. The targeted drug delivery conjugate of claim 10, wherein the conjugate comprises at least two therapeutic agents linked to the affinity molecule via the branched linker.
  12. The targeted drug delivery conjugate of claim 10, wherein the conjugate comprises two or more affinity ligands linked to the therapeutic agent via the branched linker, optionally the therapeutic agent is an anticancer agent or a cytotoxic drug.
  13. The targeted drug delivery conjugate of any of claims 1-12, wherein the linker comprises a cleavable group.
  14. The targeted drug delivery conjugate of claim 1-12, wherein two or more affinity ligands are connected together via a linker, optionally the two or more affinity ligands are each linked to a biomolecule.
  15. The targeted drug delivery conjugate of any of claims 1-14, wherein the affinity ligand is linked to two or more biomolecules, optionally a first biomolecule is covalently linked to the affinity ligand and a second biomolecule is non-covalently linked to the affinity ligand.
  16. The targeted drug delivery conjugate of claim 15, wherein the biomolecules comprise the targeting ligand, the therapeutic agent, or a combination thereof.
  17. A pharmaceutical composition comprising a targeted drug delivery conjugate of any of claims 1-16 and a pharmaceutically acceptable carrier.
  18. A targeted drug delivery conjugate of any of claims 1-16 for use in treatment of cancer.
  19. A targeted drug delivery conjugate of any of claims 1-16 for use as a medicament.

Description

CROSS-REFERENCE TO RELATED APPLICATION This application claims benefit under one or more of 35 U.S.C. § 119(a)-119(d) of Indian Patent Application No. 0732/DEL/2014, filed March 12, 2014. TECHNICAL FIELD The present invention relates to targeted drug delivery compositions and methods of making and use thereof. BACKGROUND One of the major limitations in therapy today is the toxicity or side effect of drugs. The maximum tolerated dose of a drug can thus be a hindrance for many therapies including those for cancer. There is a need for conjugates that specifically bind to a disease specific target and release the drug at the disease site. Targeted drug delivery using antibodies, for example, has been investigated extensively (R. V. J. Chari, "Targeted cancer therapy: conferring specificity to cytotoxic drugs.," Accounts of chemical research, vol. 41, no. 1, pp. 98-107, Jan. 2008). There are currently two antibody drug conjugates (ADCs) on the market for cancer therapy namely KADCYLA™ and ADCETRIS™. They both use a cytotoxic drug covalently conjugated to an antibody through a cleavable linker. Protein A is a small bacterial protein that has an affinity for the Fc region of IgG class of antibodies (T. Moks, L. Abrahmsén, B. Nilsson, U. Hellman, J. Sjöquist, and M. Uhlén, "Staphylococcal protein A consists of five IgG-binding domains.," European journal of biochemistry / FEBS, vol. 156, no. 3, pp. 637-43, May 1986). The domain that non-covalently binds to the Fc region is already known and is used for monoclonal antibody chromatographic purification extensively (S. Hober, K. Nord, and M. Linhult, "Protein A chromatography for antibody purification.," Journal of chromatography. B, Analytical technologies in the biomedical and life sciences, vol. 848, no. 1, pp. 40-7, Mar. 2007). Several protein A mimetics and small molecules have been explored in the past to replace protein A chromatography such as triazines, 4-mercaptoethyl pyridine (4-MEP), peptides (VS. Kabir, "Immunoglobulin purification by affinity chromatography using protein A mimetic ligands prepared by combinatorial chemical synthesis.," Immunological investigations, vol. 31, no. 3-4, pp. 263-78, 2002) etc. They all have affinity for the Fc region similar to protein A but each offering some advantage over the conventional protein A (S. Ghose, B. Hubbard, and S. M. Cramer, "Evaluation and comparison of alternatives to Protein A chromatography Mimetic and hydrophobic charge induction chromatographic stationary phases.," Journal of chromatography. A, vol. 1122, no. 1-2, pp. 144-52, Jul. 2006). 4-MEP and triazines have also been investigated for treatment of autoimmune diseases (J. Ren, L. Jia, L. Xu, X. Lin, Z. Pi, and J. Xie, "Removal of autoantibodies by 4-mercaptoethylpyridine-based adsorbent.," Journal of chromatography. B, Analytical technologies in the biomedical and life sciences, vol. 877, no. 11-12, pp. 1200-4, Apr. 2009 and B. Zacharie, S. D. Abbott, J.-F. Bienvenu, A. D. Cameron, J. Cloutier, J.-S. Duceppe, A. Ezzitouni, D. Fortin, K. Houde, C. Lauzon, N. Moreau, V. Perron, N. Wilb, M. Asselin, A. Doucet, M.-E. Fafard, D. Gaudreau, B. Grouix, F. Sarra-Bournet, N. St-Amant, L. Gagnon, and C. L. Penney, "2,4,6-Trisubstituted Triazines As Protein a Mimetics for the Treatment of Autoimmune Diseases.," Journal of medicinal chemistry, vol. 53, no. 3, pp. 1138-45, Feb. 2010). Some of the peptides, owing to their affinity for the antibody, have also been used for targeting nanoparticles for drug delivery (H. J. Kang, Y. J. Kang, Y.-M. Lee, H.-H. Shin, S. J. Chung, and S. Kang, "Developing an antibody-binding protein cage as a molecular recognition drug modular nanoplatform.," Biomaterials, vol. 33, no. 21, pp. 5423-30, Jul. 2012 and US Patent Publication No. 2011/0312877, and European Patent Application No. EP 2 093 287 A1). The targeting antibody directs the nanoparticles in close proximity to the target site wherein the nanoparticle can deliver its cargo. Non-covalent interactions between the linker and drug have been employed to conserve the activity of the drug U.S. Patent No. 5,420,105. Biotin labelling of biomolecules has been reported for affinity-based diagnostics (US 2001/0023288 A1) wherein the affinity of biotin towards streptadivin is employed. The binding site on IgG of the different affinity molecules has been found to be different from each other. Binding site for 4-MEP on IgG Fc has been computationally determined previously (Lin, D.-Q., Tong, H., Wang, H. & Yao, S. Molecular insight into the ligand-IgG interactions for 4-mercaptoethyl-pyridine based hydrophobic charge-induction chromatography. J. Phys. Chem. B 116, 1393-400 (2012).) Binding site of traizine on IgG Fc has also been similarly determined computationally (Branco, R. J. F., Dias, A. M. G. C. & Roque, A. C. A. Understanding the molecular recognition between antibody fragments and protein A biomimetic ligand. J. Chromatogr. A 1244, 106-15 (2012).). US 2011/312877 A1 discloses a t