Sorrento Therapeutics Inc (SRNE)

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Patent application for an ADC utilizing derivatives of amanitin(from Green Death Cap Mushroom )

Antibody drug conjugates having derivatives of amatoxin as the drug
May 31, 2017 - Sorrento Therapeutics, Inc.
There is disclosed derivatives of amanitin conjugated to a targeting antibody to form an ADC (antibody drug conjugate).

This patent application claims priority to U.S. provisional patent application 62/343,825, filed May 31, 2016, the contents of which are incorporated herein by reference.

TECHNICAL FIELD
The present disclosure provides derivatives of amanitin conjugated to a targeting antibody to form an ADC (antibody drug conjugate).

BACKGROUND
The amatoxins are rigid bicyclic peptides having eight amino acid units. These compounds are isolated from a variety of mushroom species (e.g., Amanita phalloides (also known as green death cap mushroom), Galerina marginata, Lepiota brunneo-incamata) or are prepared synthetically. Different mushroom species contain varying amounts of different Amatoxin family members. A member of this family, alpha-amanitin, is known to be an inhibitor of eukaryotic RNA polymerase II (EC2.7.7.6) and to a lesser degree, RNA polymerase III, thereby inhibiting transcription and protein biosynthesis. Wieland (1983) Int. J. Pept. Protein Res. 22(3):257-276. Alpha-amanitin binds non-covalently to RNA polymerase II and dissociates slowly, making enzyme recovery unlikely. Prolonged inhibition of transcription is thought to induce cellular apoptosis.

Exemplary amatoxins include

The use of antibody-drug conjugates (ADCs) for the local delivery of cytotoxic or cytostatic agents, including drugs that kill or inhibit tumor cells, allows targeted delivery of the drug moiety to tumors, and intracellular accumulation therein. Syrigos and Epenetos (1999) Anticancer Res. 19:605-614; Niculescu-Duvaz and Springer (1997) Adv. Drug Delivery Rev. 26:151-172; U.S. Pat. No. 4,975,278; Baldwin et al. (1986) Lancet (Mar. 15, 1986):603-05; Thorpe (1985) “Antibody Carriers of Cytotoxic Agents in Cancer Therapy: A Review,” in Monoclonal Antibodies '84: Biological and Clinical Applications, A. Pinchera et al. (eds.), pp. 475-506. This type of delivery mechanism helps to minimize toxicity to normal cells that may occur from systemic administration of unconjugated drug agents. The toxins may cause their cytotoxic and cytostatic effects through a variety of mechanisms including tubulin binding, DNA binding, or topoisomerase inhibition. Both polyclonal antibodies and monoclonal antibodies have been reported as useful in these strategies. Rowland et al. (1986) Cancer Immunol. Immunother. 21:183-87. Toxins used in antibody-toxin conjugates include radioisotopes, bacterial toxins such as diphtheria toxin, plant toxins such as ricin, fungal toxins such as amatoxins (WO2010/115629, WO2012/041504 or WO2012/119787), and small molecule toxins such as geldanamycin (Mandler et al. (2000) J. Natl. Cancer Inst. 92(19):1573-1581; Mandler et al. (2000) Bioorg. Med. Chem. Lett. 10:1025-1028; Mandler et al. (2002) Bioconjugate Chem. 13:786-791), maytansinoids (EP 1391213; Liu et al. (1996) Proc. Natl. Acad. Sci. USA 93:8618-8623), calicheamicin (Lode et al. (1998) Cancer Res. 58:2928; Hinman et al. (1993) Cancer Res. 53:3336-3342), daunomycin, doxorubicin, methotrexate, and vindesine (Rowland et al. (1986), supra).

Several antibody-drug conjugates have shown promising results against cancer in clinical trials, including ZEVALIN® (ibritumomab tiuxetan, Biogen/Idec), an antibody-radioisotope conjugate composed of a murine IgG1 kappa monoclonal antibody (directed against the CD20 antigen found on the surface of normal and malignant B lymphocytes) connected with an 111In or 90Y radioisotope via a thiourea linker-chelator.

The use of antibody-drug conjugates (ADCs) for the local delivery of cytotoxic or cytostatic agents, including drugs that kill or inhibit tumor cells, allows targeted delivery of the drug moiety to tumors, and intracellular accumulation therein. This type of delivery mechanism helps to minimize toxicity to normal cells that may occur from systemic administration of unconjugated drug agents. The toxins may cause their cytotoxic and cytostatic effects through a variety of mechanisms including tubulin binding.
As such, there remains a need for potent RNA polymerase inhibitor antibody conjugates with desirable pharmaceutical properties.
SUMMARY
The present disclosure provides improved amatoxin derivatives used in an ADC (antibody drug conjugate) structure.