COMBINATION OF CD33 ANTIBODY DRUG CONJUGATES WITH CHEMOTHERAPEUTIC AGENTS

Abstract

This invention relates to treatment of cancer using a CD33 antibody drug conjugate in combination with chemotherapeutic agents.

Claims

1. An induction-consolidation method of treating CD33 expressing acute myeloid leukemia (AML) in a subject in need of such treatment, the method comprising the step of administering cytarabine, an anthracycline antibiotic, and 10 ?g/kg of a CD33 antibody drug conjugate (ADC), wherein the CD33-ADC comprises a humanized 2H12 antibody and a PBD cytotoxic agent.

2. The method of claim 1, wherein the PBD cytotoxic agent has the formula ##STR00010##

3. The method of claim 1, wherein the anthracycline antibiotic is daunorubicin.

4. The method of claim 1, wherein the anthracycline antibiotic is idarubicin.

5. The method of claim 1, wherein the CD33-ADC is administered at a concentration of about 10 ?g/kg.

6. The method of claim 1, wherein the CD33-ADC is administered at a concentration of about 10 ?g/kg.

7. The method of claim 1, wherein the induction-consolidation method is followed by a maintenance treatment.

8. The method of claim 7, wherein the maintenance treatment is administration of the CD33-ADC at a concentration of about 5 ?g/kg.

9. An induction method of treating CD33 expressing acute myeloid leukemia (AML) in a subject in need of such treatment, the method comprising the step of administering cytarabine, an anthracycline antibiotic, and a CD33 antibody drug conjugate (ADC), wherein the CD33-ADC comprises a humanized 2H12 antibody and a PBD cytotoxic agent, and wherein in 20 ?g/kg of the CD33-ADC is administered on day one of a seven-day induction cycle and 10 ?g/kg of the CD33-ADC is administered on day four of a seven-day induction cycle.

10. The method of claim 9, wherein the PBD cytotoxic agent has the formula ##STR00011##

11. The method of claim 9, wherein the anthracycline antibiotic is daunorubicin and is administered at 60 mg/m.sup.2/day on induction days 1-3.

12. The method of claim 9, wherein the cytarabine is administered at 100 mg/m.sup.2/day on induction days 1-7.

13. The method of claim 9, wherein the humanized 2H12 antibody comprises a light chain variable region of SEQ ID NO:1 and a heavy chain variable region of SEQ ID NO:2.

14. An induction method of treating CD33 expressing acute myeloid leukemia (AML) in a subject in need of such treatment, the method comprising the step of administering cytarabine, an anthracycline antibiotic, and a CD33 antibody drug conjugate (ADC), wherein the CD33-ADC comprises a humanized 2H12 antibody and a PBD cytotoxic agent, and wherein in 30 ?g/kg of the CD33-ADC is administered on day one of a seven-day induction cycle.

15. The method of claim 14, wherein the PBD cytotoxic agent has the formula ##STR00012##

16. The method of claim 14, wherein the anthracycline antibiotic is daunorubicin and is administered at 60 mg/m.sup.2/day on induction days 1-3.

17. The method of claim 14, wherein the cytarabine is administered at 100 mg/m.sup.2/day on induction days 1-7.

18. The method of claim 14, wherein the humanized 2H12 antibody comprises a light chain variable region of SEQ ID NO:1 and a heavy chain variable region of SEQ ID NO:2.

19. An induction method of treating CD33 expressing acute myeloid leukemia (AML) in a subject in need of such treatment, the method comprising the step of administering cytarabine, an anthracycline antibiotic, and a CD33 antibody drug conjugate (ADC), wherein the CD33-ADC comprises a humanized 2H12 antibody and a PBD cytotoxic agent, and wherein in 40 ?g/kg of the CD33-ADC is administered on day one of a seven day induction cycle.

20. The method of claim 19, wherein the PBD cytotoxic agent has the formula ##STR00013##

21. The method of claim 19, wherein the anthracycline antibiotic is daunorubicin and is administered at 60 mg/m.sup.2/day on induction days 1-3.

22. The method of claim 19, wherein the cytarabine is administered at 100 mg/m.sup.2/day on induction days 1-7.

23. The method of claim 19, wherein the humanized 2H12 antibody comprises a light chain variable region of SEQ ID NO:1 and a heavy chain variable region of SEQ ID NO:2.

Description

DETAILED DESCRIPTION

[0048] This invention demonstrates optimal dosing of SGN-CD33A, a CD33-antibody drug conjugate (CD33-ADC), i.e., h2H12 antibody conjugated to a PBD, with cytarabine and an anthracycline antibiotic or an anthracenedione. Preferred anthracyclines include, e.g., daunorubicin, doxorubicin, idarubicin or mitoxantrone.

I. CD33 antibody drug conjugates

[0049] A. Anti-CD33 Antibodies

[0050] The anti-CD33 antibody disclosed herein is the humanized 2H12 antibody (h2H12). The murine 2H12 antibody was raised in mice, using the human CD33 protein as an immunogen. After making hybridomas from the spleens of the immunized mice, followed by screening for CD33 binding activity, the murine 2H12 antibody was selected for humanization. The h2H12 antibody was derived from the murine 2H12 antibody. The humanization procedure is disclosed in PCT publication WO 2013/173,496; which is herein incorporated by reference for all purposes. The variable region sequences of the h2H12 light and heavy chains are provided as SEQ ID NO:1 and SEQ ID NO:2, respectively.

[0051] The h2H12 antibody comprises human constant regions. Sequences of human constant regions are provided in the sequence listing. The heavy chain constant region of h2H12 includes a substitution mutation, S239C, to facilitate conjugation of a drug-linker to the antibody. The sequence of a human constant region comprising the S239C mutation is provided at SEQ ID NOs:6 and 7. The h2H12 antibody comprising the S239C mutation is also referred to as h2H12EC.

[0052] B. Drug Linkers

[0053] Exemplary CD33 antibody-drug conjugates include PBD based antibody-drug conjugates; i.e., antibody-drug conjugates wherein the drug component is a PBD drug.

[0054] PBDs are of the general structure:

##STR00006##

[0055] They differ in the number, type and position of substituents, in both their aromatic A rings and pyrrolo C rings, and in the degree of saturation of the C ring. In the B-ring there is either an imine (N?C), a carbinolamine(NHCH(OH)), or a carbinolamine methyl ether (NHCH(OMe)) at the N10-C11 position, which is the electrophilic centre responsible for alkylating DNA. All of the known natural products have an (S)-configuration at the chiral C11a position which provides them with a right-handed twist when viewed from the C ring towards the A ring. This gives them the appropriate three-dimensional shape for isohelicity with the minor groove of B-form DNA, leading to a snug fit at the binding site (Kohn, In Antibiotics III. Springer-Verlag, New York, pp. 3-11 (1975); Hurley and Needham-VanDevanter, Acc. Chem. Res., 19, 230-237 (1986)). The ability of PBDs to form an adduct in the minor groove enables them to interfere with DNA processing, hence their use as anti-tumor agents.

[0056] The biological activity of these molecules can be potentiated by joining two PBD units together through their C8/C-hydroxyl functionalities via a flexible alkylene linker (Bose, D. S., et al., J. Am. Chem. Soc., 114, 4939-4941 (1992); Thurston, D. E., et al., J. Org. Chem., 61, 8141-8147 (1996)). The PBD dimers are thought to form sequence-selective DNA lesions such as the palindromic 5-Pu-GATC-Py-3 interstrand cross-link (Smellie, M., et al., Biochemistry, 42, 8232-8239 (2003); Martin, C., et al., Biochemistry, 44, 4135-4147) which is thought to be mainly responsible for their biological activity.

[0057] In some embodiments, PBD based antibody-drug conjugates comprise a PBD dimer linked to an anti-CD33 antibody. The monomers that form the PBD dimer can be the same or different, i.e., symmetrical or unsymmetrical. The PBD dimer can be linked to the anti-CD33 antibody at any position suitable for conjugation to a linker. For example, in some embodiments, the PBD dimer will have a substituent at the C2 position that provides an anchor for linking the compound to the anti-CD33 antibody. In alternative embodiments, the N10 position of the PBD dimer will provide the anchor for linking the compound to the anti-CD33 antibody.

[0058] Typically the PBD based antibody-drug conjugate comprises a linker between the PBD drug and the anti-CD33 antibody. The linker may comprise a cleavable unit (e.g., an amino acid or a contiguous sequence of amino acids that is a target substrate for an enzyme) or a non-cleavable linker (e.g., linker released by degradation of the antibody). The linker may further comprise a maleimide group for linkage to the antibody, e.g., maleimidocaproyl. The linker may, in some embodiments, further comprise a self-immolative group, such as, for example, a p-aminobenzyl alcohol (PAB) unit.

[0059] An exemplary PBD for use as a conjugate is described in International Application No. WO 2011/130613 and is as follows wherein the wavy line indicates the site of attachment to the linker:

##STR00007##

or a pharmaceutically acceptable salt thereof. An exemplary linker is as follows wherein the wavy line indicates the site of attachment to the drug and the antibody is linked via the maleimide group.

##STR00008##

[0060] Exemplary PBDs based antibody-drug conjugates include antibody-drug conjugates as shown below wherein Ab is an antibody as described herein:

##STR00009##

or a pharmaceutically acceptable salt thereof. The drug loading is represented by p, the number of drug-linker molecules per antibody. Depending on the context, p can represent the average number of drug-linker molecules per antibody, also referred to the average drug loading. The variable p ranges from 1 to 20 and is preferably from 1 to 8. In some preferred embodiments, when p represents the average drug loading, p ranges from about 2 to about 5. In some embodiments, p is about 2, about 3, about 4, or about 5. In some aspects, the antibody is conjugated to the drug linker via a sulfur atom of a cysteine residue that is engineered into the antibody. In some aspects, the cysteine residue is engineered into the antibody at position 239 (IgG1) as determined by the EU index (Kabat, Sequences of Proteins of Immunological Interest (National Institutes of Health, Bethesda, Md., 1987 and 1991).

[0061] C. CD33-ADCs

[0062] As used herein a CD33-ADC refers to an ADC that comprises an h2H12 antibody conjugated to a PBD molecule. The antibody portion comprises the variable light chain region of SEQ ID NO:1 and the variable heavy chain region of SEQ ID NO:2. The constant region is a human IgG1 constant region. The heavy chain constant region has a substitution mutation at amino acid 239 using Kabat numbering, i.e., S239C. The cysteine residue at position 239 is the point of attachment for the PBD molecule. The structure of the antibody, the linker and the PBD molecule is shown above. Methods to make the CD33-ADC are disclosed in PCT publication WO 2013/173,496 and PCT publication WO 2011/130613, both of which are incorporated by reference for all purposes.

II. 7 Plus 3 Chemotherapy

[0063] AML is frequently treated with first line induction therapy known as 7 plus 3. 7 plus 3 refers to the duration of the chemotherapy, i.e., seven days of standard-dose cytarabine, and three days of an anthracycline antibiotic or an anthracenedione. Preferred anthracyclines include, e.g., daunorubicin, doxorubicin, idarubicin or mitoxantrone. After blood count recovery, consolidation therapy follows with up to four consolidation cycles of seven days duration. Consolidation therapy includes administration of cytarabine and the CD33-ADC. Maintenance therapy can follow the induction-consolidation regimen. Maintenance therapy includes administration of the CD33-ADC.

III. Treatment of Acute Myeloid Leukemia (AML)

[0064] CD33-ADCs in combination with 7+3 induction-consolidation therapy can be used to treat acute myeloid leukemia (AML), preferably AML that has detectable levels of CD33 measured at either the protein (e.g., by immunoassay using one of the exemplified antibodies) or mRNA level. Some such AML cells show elevated levels of CD33 relative to noncancerous tissue of the same type, preferably from the same patient. An exemplary level of CD33 on AML samples amenable to treatment is 5000-150000 CD33 molecules per cell, although higher or lower levels can be treated. Optionally, a level of CD33 in a cancer is measured before performing treatment.

[0065] The combination of CD33-ADC with 7+3 induction-consolidation therapy can be applied to patients who are treatment na?ve, who are refractory to conventional treatments (e.g., chemotherapy), or who have relapsed following a response to such treatments. Some cancer cells develop resistance to a therapeutic agent after increasing expression of a protein increases efflux of the therapeutic agent out of the cancer cell. Such proteins include P-glycoprotein, multidrug resistance-associated protein, lung resistance-related protein, and breast cancer resistance protein. Detection of drug resistance in cancer cells can be performed by those of skill. Antibodies or assays that detect efflux proteins are commercially available from, e.g., Promega, Millipore, Abcam, and Sigma-Aldrich. In one embodiment, a CD33-ADC in combination with a hypomethylating agent is used to treat a subject with a multi-drug resistant, CD33-positive AML.

[0066] In some embodiments the combination of a CD33-ADC with 7+3 induction-consolidation therapy is used to treat younger, fit patients who are able to withstand the toxicities associated with induction chemotherapy. These patients are often younger than 65, however patients with younger physiologic age who are older than age 65 may also receive induction therapy with a CD33-ADC with 7+3. In some embodiments, the CD33-ADC with 7+3 induction-consolidation therapy is administered to patients younger than 65 years old.

IV. Dosage and Administration

[0067] Pharmaceutical compositions for parenteral administration are preferably sterile and substantially isotonic and manufactured under GMP conditions. Pharmaceutical compositions can be provided in unit dosage form (i.e., the dosage for a single administration). Pharmaceutical compositions can be formulated using one or more physiologically acceptable carriers, diluents, excipients or auxiliaries. The formulation depends on the route of administration chosen. For injection, antibodies can be formulated in aqueous solutions, preferably in physiologically compatible buffers such as Hank's solution, Ringer's solution, or physiological saline or acetate buffer (to reduce discomfort at the site of injection). The solution can contain formulatory agents such as suspending, stabilizing and/or dispersing agents. Alternatively, antibodies can be in lyophilized form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use. Formulations for the CD33-ADC comprising h2H12 antibody and a PBD molecule are disclosed e.g., at PCT/US2014/024466.

[0068] The CD33-ADC is administered intravenously, as is cytarabine, and the anthracycline antibiotic, e.g., daunorubicin, doxorubicin, idarubicin or mitoxantrone.

[0069] The combination of the CD33-ADC with 7+3 induction-consolidation therapy is dosed using an induction period followed by a consolidation period. In one embodiment, the induction period is seven days. The CD33-ADC is administered on induction days 1 and 4 at 10 ?g/kg or 20 ?g/kg; cytarabine is administered at 100 mg/m.sup.2/day on induction days 1-7, and daunorubicin is administered at 60 mg/m.sup.2/day on induction days 1-3. The consolidation period includes up to four cycles of seven days. The CD33-ADC is administered on consolidation day 1 at 10 ?g/kg or 20 ?g/kg; cytarabine is administered at 3 gm/m.sup.2/day on consolidation days 1, 3, and 5. The number of consolidation cycles is determined by the physician.

[0070] The combination of the CD33-ADC with 7+3 induction-consolidation therapy is dosed using an induction period followed by a consolidation period. In one embodiment, the induction period is seven days. The CD33-ADC is administered on induction day 1 at 30 ?g/kg or 40 ?g/kg; cytarabine is administered at 100 mg/m.sup.2/day on induction days 1-7, and daunorubicin is administered at 60 mg/m.sup.2/day on induction days 1-3. The consolidation period includes up to four cycles of seven days. The CD33-ADC is administered on consolidation day 1 at 10 ?g/kg or 20 ?g/kg; cytarabine is administered at 3 gm/m.sup.2/day on consolidation days 1, 3, and 5. The number of consolidation cycles is determined by the physician.

[0071] In another embodiment, the induction period is seven days. The CD33-ADC is administered on induction day 1 or induction day 4 at 10 ?g/kg or 20 ?g/kg; cytarabine is administered at 100 mg/m.sup.2/day on induction days 1-7, and daunorubicin is administered at 60 mg/m.sup.2/day on induction days 1-3. The consolidation period includes up to four cycles of seven days. The CD33-ADC is administered on consolidation day 1 at 10 ?g/kg or 20 ?g/kg; cytarabine is administered at 3 gm/m.sup.2/day on consolidation days 1, 3, and 5. The number of consolidation cycles is determined by the physician.

[0072] In a further embodiment, the induction period is seven days. The CD33-ADC is administered on induction days 1 and 4 at 10 ?g/kg or 20 ?g/kg; cytarabine is administered at 100 mg/m.sup.2/day on induction days 1-7, and idarubicin is administered at 12 mg/m.sup.2/day on induction days 1-3. The consolidation period includes up to four cycles of seven days. The CD33-ADC is administered on consolidation day 1 at 10 ?g/kg or 20 ?g/kg; cytarabine is administered at 3 gm/m.sup.2/day on consolidation days 1, 3, and 5. The number of consolidation cycles is determined by the physician.

[0073] The combination of the CD33-ADC with 7+3 induction therapy is dosed using an induction period. In one embodiment, the induction period is seven days. The CD33-ADC is administered on induction day 1 at 20 ?g/kg and induction day 4 at 10 ?g/kg; cytarabine is administered at 100 mg/m.sup.2/day on induction days 1-7, and daunorubicin is administered at 60 mg/m.sup.2/day on induction days 1-3.

[0074] The combination of the CD33-ADC with 7+3 induction therapy is dosed using an induction period. In one embodiment, the induction period is seven days. The CD33-ADC is administered on induction day 1 at 30 or 40 ?g/kg; cytarabine is administered at 100 mg/m.sup.2/day on induction days 1-7, and daunorubicin is administered at 60 mg/m.sup.2/day on induction days 1-3.

[0075] An induction-consolidation regimen can be followed by maintenance dosing of the CD33-ADC. The maintenance dose of the CD33-ADC is typically given in forty-two day cycles for up to eight cycles. The CD33 ADC is administered at 5 ?g/kg on day one of the cycle. The number of maintenance cycles is determined by the physician.

Examples

[0076] The following examples are offered to illustrate, but not to limit the claimed invention.

Example 1

CD33-ADC in Combination with 7+3 Chemotherapy for Treatment of Patients with AML

Methods

[0077] A combination of a CD33-ADC with a standard induction therapy is administered to patients with AML. The seven day induction period includes administration of cytarabine at 100 mg/m.sup.2/day on induction days 1-7, administration of the CD33-ADC on induction day 1 at 10 ?g/kg or 20 ?g/kg, and daunorubicin is administered at 60 mg/m.sup.2/day on induction days 1-3. A consolidation period of up to four cycles of seven days follows the induction period. The consolidation period includes administration of the CD33-ADC is on consolidation day 1 at 10 ?g/kg or 20 ?g/kg; cytarabine is administered at 3 gm/m.sup.2/day on consolidation days 1, 3, and 5. The consolidation period is followed by a maintenance period of forty-two day cycles for up to eight cycles. The CD33-ADC is administered at 5 ?g/kg on day one of the maintenance cycle. Patients with clinical benefit may continue treatment until relapse or unacceptable toxicity. Investigator assessment of response is per IWG criteria; CRi requires either platelet count of ?100,000/?L or neutrophils of >1,000/?L (Cheson 2003).

[0078] A combination of a CD33-ADC with a standard induction therapy is administered to patients with AML. The seven day induction period includes administration of cytarabine at 100 mg/m.sup.2/day on induction days 1-7, administration of the CD33-ADC on induction day 4 at 10 ?g/kg or 20 ?g/kg, and daunorubicin is administered at 60 mg/m.sup.2/day on induction days 1-3. A consolidation period of up to four cycles of seven days follows the induction period. The consolidation period includes administration of the CD33-ADC is on consolidation day 1 at 10 ?g/kg or 20 ?g/kg; cytarabine is administered at 3 gm/m.sup.2/day on consolidation days 1, 3, and 5. The consolidation period is followed by a maintenance period of forty-two day cycles for up to eight cycles. The CD33 ADC is administered at 5 ?g/kg on day one of the maintenance cycle. Patients with clinical benefit may continue treatment until relapse or unacceptable toxicity. Investigator assessment of response is per IWG criteria; CRi requires either platelet count of ?100,000/?L or neutrophils of >1,000/?L (Cheson 2003).

[0079] A combination of a CD33-ADC with a standard induction therapy is administered to patients with AML. The seven day induction period includes administration of cytarabine at 100 mg/m.sup.2/day on induction days 1-7, administration of the CD33-ADC on induction days 1 and 4 at 10 ?g/kg or 20 ?g/kg, and idarubicin is administered at 12 mg/m.sup.2/day on induction days 1-3. A consolidation period of up to four cycles of seven days follows the induction period. The consolidation period includes administration of the CD33-ADC is on consolidation day 1 at 10 ?g/kg or 20 ?g/kg; cytarabine is administered at 3 gm/m.sup.2/day on consolidation days 1, 3, and 5. The consolidation period is followed by a maintenance period of forty-two day cycles for up to eight cycles. The CD33 ADC is administered at 5 ?g/kg on day one of the maintenance cycle. Patients with clinical benefit may continue treatment until relapse or unacceptable toxicity. Investigator assessment of response is per IWG criteria; CRi requires either platelet count of >100,000/?L or neutrophils of >1,000/?L (Cheson 2003).

[0080] A combination of a CD33-ADC with a standard induction therapy is administered to patients with AML. The seven day induction period includes administration of cytarabine at 100 mg/m.sup.2/day on induction days 1-7, administration of the CD33-ADC on induction day 1 at 30 ?g/kg or 40 ?g/kg, and daunorubicin is administered at 60 mg/m.sup.2/day on induction days 1-3. A consolidation period of up to four cycles of seven days follows the induction period. The consolidation period includes administration of the CD33-ADC is on consolidation day 1 at 10 ?g/kg or 20 ?g/kg; cytarabine is administered at 3 gm/m.sup.2/day on consolidation days 1, 3, and 5. The consolidation period is followed by a maintenance period of forty-two day cycles for up to eight cycles. The CD33-ADC is administered at 5 ?g/kg on day one of the maintenance cycle. Patients with clinical benefit may continue treatment until relapse or unacceptable toxicity. Investigator assessment of response is per IWG criteria; CRi requires either platelet count of ?100,000/?L or neutrophils of ?1,000/?L (Cheson 2003).

[0081] Split-dose cohort: 42 patients (med age 45.5 yrs [range, 18-65]) were treated with 33A on D1 and 4 (10+10 [n=4] or 20+10 [n=38] mcg/kg) with 7+3. Most patients had intermediate (50%) or adverse (36%) cytogenetic risk (MRC) and 19% had secondary AML. 2 patients had hematologic DLTs (lack of recovery of platelets [25K] and/or ANC [500] by D42) and 20+10 mcg/kg was determined to be MTD. All patients had G4 myelosuppression, and the med time to count recovery from D1 of therapy in patients who achieved CR/CRi was 4.9 wks for neutrophils (?1K) and 5.1 wks for platelets (?100K). No non-hematologic treatment-emergent adverse events (TEAEs)?G3 were reported in >10% of patients; non-hematologic TEAEs of any grade occurring in >20% of patients were nausea (62%), diarrhea, constipation (38% each), headache, hypokalemia (24% each), decreased appetite, fatigue, hypertension, and stomatitis (21% each). Of the 42 efficacy evaluable (EE) patients, best responses include 25 CR (60%), 7 CRi (17%), and 5 morphologic leukemia-free state (mLFS; 12%) with a CR+CRi (CRc) rate of 76%; 23 of 25 (94%) of responses were achieved with 1 cycle of therapy. Of the patients who achieved blast clearance (CR+CRi+mLFS), 77% (27/35) achieved an MRD negative status.

[0082] Single-dose cohort: To date, 25 patients (med age 58 yrs [range, 38-65]) were treated with 33A dosed on D1 (30 [n=14] or 40 [n=11] mcg/kg) with 7+3. Patients had intermediate (48%) or adverse (36%) cytogenetic risk and 16% had secondary AML. All patients had G4 myelosuppression and the med time to count recovery from D1 of therapy was 4.1 wks for neutrophils (>1K) and 5.9 wks for platelets (>100K) in patients who achieved CR/CRi. 2 patients had hematologic DLTs, 1 each at 30 and 40 mcg/kg. No non-hematologic TEAEs?G3 were reported in >10% of patients and non-hematologic TEAEs were consistent with those seen in the D1 and 4 schedule. Of the 23 EE patients, best responses include 11 CR (46%), 6 CRi (25%), and 4 mLFS (17%) with a CRc rate of 71%; all responses were achieved with 1 cycle of therapy. Of the patients who achieved blast clearance, 89% (17/19) achieved a MRD negative status.

[0083] Across schedules (N=67), the CRc rate was 72% and 79% (44/56) patients with blast clearance achieved MRD negativity. The 30- and 60-day mortality rates were 1% and 7%, respectively. Median OS is not yet reached for either schedule and 52 patients (78%) were alive at the time of this analysis. Total exposure to 33A was characterized for the different dosing regimens and pharmacokinetic data demonstrate rapid elimination of 33A.

[0084] It is understood that the examples and embodiments described herein are for illustrative purposes only and that various modifications or changes in light thereof will be suggested to persons skilled in the art and are to be included within the spirit and purview of this application and scope of the appended claims. All publications, patents, and patent applications cited herein are hereby incorporated by reference in their entirety for all purposes.