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Last Updated: March 29, 2024

Claims for Patent: 9,856,314


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Summary for Patent: 9,856,314
Title:Activatable antibodies having non-binding steric moieties and methods of using the same
Abstract: The invention relates generally to activatable antibodies and methods of making and using these activatable antibodies in a variety of therapeutic, diagnostic and prophylactic indications.
Inventor(s): Lowman; Henry Bernard (El Granada, CA), Liu; Shouchun (Burlingame, CA)
Assignee: CYTOMX THERAPEUTICS, INC. (South San Francisco, CA)
Application Number:13/924,207
Patent Claims:1. A composition comprising an activatable antibody comprising: a binding partner (BP) for a non-binding steric moiety (NB), wherein the BP is an albumin-binding polypeptide comprising the amino acid sequence of SEQ ID NO: 1, and the NB comprises a serum albumin; a cleavable linker (CL); and an antibody or antibody fragment (AB) that binds specifically to a target, wherein the target is an epidermal growth factor receptor (EGFR), wherein the AB comprises the six complementarity determining regions (CDR) of cetuximab, wherein: the BP is a polypeptide that binds to the NB when exposed thereto; the NB does not bind specifically to the AB; the CL is a polypeptide that comprises a substrate (S) for an enzyme, wherein the enzyme is urokinase plasminogen activator (uPa); the CL is positioned in the activatable antibody such that in an uncleaved state in the presence of the NB, the NB when bound to the BP interferes with binding of the AB to the target and in a cleaved state, the NB when bound to the BP does not interfere with binding of the AB to the target; and the NB and the BP do not inhibit cleavage of the CL by the enzyme.

2. The composition of claim 1, wherein the BP of the activatable antibody is bound to the NB.

3. The composition of claim 1, wherein the composition comprises the NB, where the NB is co-formulated with the activatable antibody comprising the BP, the CL, and the AB.

4. The composition of claim 1, wherein the NB is recruited by the BP of the activatable antibody in vivo.

5. The composition of claim 1, wherein the NB is a soluble, globular protein.

6. The composition of claim 1, wherein the NB is a protein that circulates in the bloodstream.

7. The composition of claim, 1 wherein the uPa is co-localized with the target in a tissue, and wherein the uPa cleaves the CL in the activatable antibody when the activatable antibody is exposed to the uPa.

8. The composition of claim 1, wherein the activatable antibody in the uncleaved state has the structural arrangement from N-terminus to C-terminus as follows: BP-CL-AB or AB-CL-BP.

9. The activatable antibody of claim 1, wherein the composition has the structural arrangement from N-terminus to C-terminus as follows when the activatable antibody is in the uncleaved state: NB:BP-CL-AB or AB-CL-BP:NB.

10. The composition of claim 7, wherein the CL comprises a substrate (S) and a first flexible portion (FP1), or a substrate (S) and second flexible portion (FP2), or a substrate (S), a first flexible portion (FP1) and a second flexible portion (FP2).

11. The composition of claim 7, wherein the CL comprises a substrate (S) and a first flexible portion (FP1), a substrate (S) and second flexible portion (FP2), or a substrate (S), a first flexible portion (FP1) and a second flexible portion (FP2), and wherein the activatable antibody in the uncleaved state has the structural arrangement from N-terminus to C-terminus as follows: BP-FP1-S-FP2-AB, AB-FP2-S-FP1-BP, NB:BP-FP1-S-FP2-AB or AB-FP2-S-FP1-BP:NB.

12. The composition of claim 10, wherein the two flexible portions of the CL need not be identical to each other.

13. The composition of claim 10, wherein each of FP1 and FP2 is a peptide of about 1 to 20 amino acids in length.

14. The composition of claim 10, wherein at least one of FP1 or FP2 comprises an amino acid sequence selected from the group consisting of (GS)n, (GGS)n, (GSGGS)n (SEQ ID NO: 5) and (GGGS)n (SEQ ID NO: 6), where n is an integer of at least one.

15. The composition of claim 10, wherein at least one of FP1 or FP2 comprises an amino acid sequence selected from the group consisting of GGSG (SEQ ID NO: 7), GGSGG (SEQ ID NO: 8), GSGSG (SEQ ID NO: 9), GSGGG (SEQ ID NO: 10), GGGSG (SEQ ID NO: 11), and GSSSG (SEQ ID NO: 12).

16. The composition of claim 1, wherein the CL is a polypeptide of up to 50 amino acids in length.

17. The composition of claim 1, wherein the AB is an antigen binding fragment selected from the group consisting of a Fab fragment, a F(ab').sub.2 fragment, a scFv, a scAb, and a dAb.

18. The composition of claim 1, wherein the NB in the uncleaved activatable antibody reduces the ability of the AB to bind the target by at least 50%, as compared to the ability of the cleaved AB to bind the target.

19. The composition of claim 1, wherein the activatable antibody comprises an agent conjugated to the AB.

20. The composition of claim 19, wherein the agent is a therapeutic agent.

21. The composition of claim 19, wherein the agent is an antineoplastic agent.

22. The composition of claim 19, wherein the agent is a toxin or fragment thereof.

23. The composition of claim 19, wherein the agent is a detectable marker.

24. The composition of claim 19, wherein the agent is an agent selected from the group consisting of: an Auristatin, Auristatin E, Monomethyl auristatin E (MMAE), Desmethyl auristatin E (DMAE), Auristatin F, Monomethyl auristatin F (MMAF), Desmethyl auristatin F (DMAF), an Auristatin amide, Auristatin tyramine, Auristatin quinoline, a Dolastatin, Dolastatin 16 DmJ, Dolastatin 16 Dpv, a Maytansinoid, DM-1, DM-4, Duocarmycin, Alpha-amanitin, an Anthracycline, Doxorubicin, Daunorubicin, a Bryostatin, Camptothecin, 7-substituted Camptothecin, 10, 11-Difluoromethylenedioxycamptothecin, a Combretastatin, Debromoaplysiatoxin, Kahalalide-F, Discodermolide, an Ecteinascidin, Acyclovir, Vira A, Symmetrel, Nystatin, Turbostatin, a Phenstatin, Hydroxyphenstatin, Spongistatin 5, Spongistatin 7, Halistatin 1, Halistatin 2, Halistatin 3, a Modified Bryostatin, a Halocomstatin, a Pyrrolobenzimidazole (PBI), Cibrostatin6, Doxaliform, Cemadotin analogue (CemCH2-SH), Pseudomonas toxin A (PE38), Pseudomonas toxin A (ZZ-PE38), a structurally simplified analog of the marine natural product superstolide A (ZJ-101), 3beta,16beta17alpha-trihydroxycholest-5-en-22-one16-O-(2-O-4-methoxybenzo- yi-beta-D-xlopyranosyl)-(1->3)-(2-O-acetyl-alpha-L-arabinopyranoside) (OSW-1), a Topoisomerase inhibitor, Hemiasterlin, Cephalotaxine, Homoharringtonine, a Pyrrolobenzodiazepine dimer (PBD), a Functionalized pyrrolobenzodiazepene, a Calicheamicin, a Podophyllotoxin, a Taxane, a Vinca alkaloid, Fluorescein, Fluorescein isothiocyanate (FITC), Adriamycin, Cerubidine, Bleomycin, Alkeran, Velban, Oncovin, Fluorouracil, Methotrexate, Thiotepa, Bisantrene, Novantrone, Thioguanine, Procarahizine, Cytarabine, an Aminoglycoside, Streptomycin, Neomycin, Kanamycin, Amikacin, Gentamicin, Tobramycin, Streptomycin B, Spectinomycin,Ampicillin, Sulfanilamide, Polymyxin, Chloramphenicol, .sup.125I, .sup.131I, .sup.89Zr, .sup.111In, .sup.123I, .sup.131I, .sup.99mTc, .sup.201Tl, .sup.133Xe, .sup.11C, .sup.62Cu, .sup.18F, .sup.68Ga, .sup.13N, .sup.15O, .sup.38K, .sup.82Rb, .sup.99mTc (Technetium), Barium, Gold, Platinum, Tylosine, and Spectinomycin.

25. The composition of claim 19, wherein the agent is conjugated to the AB via a linker.

26. The composition of claim 25, wherein the linker is a cleavable linker.

27. A modified antibody comprising: a binding partner (BP) for a non-binding steric moiety (NB), wherein the BP is an albumin-binding polypeptide and the NB comprises a serum albumin; and an antibody (AB) that binds specifically to a target, wherein the target is an epidermal growth factor receptor (EGFR), wherein the AB comprises the six complementarity determining regions (CDR) of cetuximab, wherein: the BP binds to the NB when exposed thereto; the NB does not bind specifically to the AB; and the BP is positioned such that when the BP is bound to the NB, the NB interferes with binding of the AB to the target.

28. The composition of claim 1, wherein the substrate (S) is a polypeptide of up to 15 amino acids in length.

29. The composition of claim 1, wherein the CL comprises a first substrate (S1) and a second substrate (S2).

Details for Patent 9,856,314

Applicant Tradename Biologic Ingredient Dosage Form BLA Approval Date Patent No. Expiredate
Microbix Biosystems Inc. KINLYTIC urokinase For Injection 021846 01/16/1978 ⤷  Try a Trial 2032-06-22
Eli Lilly And Company ERBITUX cetuximab Injection 125084 02/12/2004 ⤷  Try a Trial 2032-06-22
Eli Lilly And Company ERBITUX cetuximab Injection 125084 03/28/2007 ⤷  Try a Trial 2032-06-22
>Applicant >Tradename >Biologic Ingredient >Dosage Form >BLA >Approval Date >Patent No. >Expiredate

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