Brain-targeting compositions and methods of use thereof

Abstract

The present disclosure provides methods for treating Alzheimer's disease by subcutaneous administration of high-volume or high-dose brain-targeting antibodies or antigen-binding fragments thereof, and provides compositions comprising anti-amyloid beta antibodies or antigen-binding fragments thereof.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to and the benefit of U.S. Provisional Patent Application No. 63 / 224,848, filed July 22, 2021, and U.S. Provisional Patent Application No. 63 / 227,895, filed July 30, 2021, the contents of which are incorporated by reference in their entireties into this specification.

[0002] Sequence Listing

[0002] This application contains a Sequence Listing that has been submitted electronically in XML format, which is incorporated herein by reference in its entirety. Said XML copy, created on July 21, 2022, is named 000218-0048-WO1_SL.xml and is 14,727 bytes in size. [Background technology]

[0003]

[0003] Traditional intravenous (IV) therapeutics have longer administration times, increased healthcare costs, and reduced convenience compared to subcutaneous (SC) administration. IV therapy requires administration by a skilled medical professional, typically in a hospital or clinic, limiting patient access to medications and increasing the burden on healthcare resources. SC delivery can increase patient convenience through the possibility of self-administration and / or administration in a broader range of care settings beyond hospital-based clinics, while maintaining efficacy and safety compared to IV formulations of the same drug. However, for large molecules such as monoclonal antibodies or other viscous fluids, the amount of fluid that can be administered subcutaneously is limited by extracellular matrix constraints. Historically, tolerability issues such as swelling at the injection site have limited the use of higher doses / volumes of SC administration (>10-15 mL), while reduced bioavailability is also a potential concern. These limitations mean that SC formulations may require multiple SC injections or injection sites, more frequent administration, and dose adjustments to achieve equivalent drug exposure as IV formulations. Systemic administration of therapeutic agents is also limited by the need for very high dose levels of therapeutic agents.

[0004]

[0004] There remains a need for methods and compositions for administering high doses / high volumes of therapeutic agents, particularly those that target the brain. Summary of the Invention

[0005]

[0005] The present disclosure provides compositions suitable for subcutaneous administration that include high-capacity and high-dose brain-targeting antibodies or antigen-binding fragments thereof, which are useful, for example, in the treatment of Alzheimer's disease.

[0006]

[0006] In one aspect, the present disclosure provides a method for treating Alzheimer's disease in a subject, the method comprising subcutaneously administering to the subject a composition comprising a brain-targeting antibody or antigen-binding fragment thereof, wherein the brain-targeting antibody or antigen-binding fragment thereof is at a concentration of about 130 mg / mL to about 200 mg / mL.

[0007]

[0007] In one aspect, the disclosure provides a method for treating a subject at risk for Alzheimer's disease, the method comprising subcutaneously administering to the subject a composition comprising a brain-targeting antibody or antigen-binding fragment thereof, wherein the brain-targeting antibody or antigen-binding fragment thereof is at a concentration of about 130 mg / mL to about 200 mg / mL.

[0008]

[0008] In one aspect, the present disclosure provides a method for treating cognitive impairment in a subject, the method comprising subcutaneously administering to the subject a composition comprising a brain-targeting antibody or antigen-binding fragment thereof, wherein the brain-targeting antibody or antigen-binding fragment thereof is at a concentration of about 130 mg / mL to about 200 mg / mL.

[0009] In one aspect, the disclosure provides a method for reducing cognitive impairment in a subject, the method comprising subcutaneously administering to the subject a composition comprising a brain-targeting antibody or antigen-binding fragment thereof, wherein the brain-targeting antibody or antigen-binding fragment thereof is at a concentration of about 130 mg / mL to about 200 mg / mL. In some embodiments, the cognitive impairment is mild cognitive impairment (MCI).

[0010]

[0010] In one aspect, the present disclosure provides a method for delaying the progression of Alzheimer's disease (AD) in a subject diagnosed with early or mild-to-moderate AD, the method comprising subcutaneously administering to the subject a composition comprising a brain-targeting antibody or antigen-binding fragment thereof, wherein the brain-targeting antibody or antigen-binding fragment thereof is at a concentration of about 130 mg / mL to about 200 mg / mL.

[0011]

[0011] In one aspect, the present disclosure provides a method for treating early or mild to moderate AD without increasing the risk of adverse events, the method comprising subcutaneously administering to a subject a composition comprising a brain-targeting antibody or antigen-binding fragment thereof, wherein the brain-targeting antibody or antigen-binding fragment thereof is at a concentration of about 130 mg / mL to about 200 mg / mL.

[0012]

[0012] In one aspect, the present disclosure provides a method for slowing progression in a patient diagnosed with early or mild to moderate Alzheimer's disease (AD), the method comprising subcutaneously administering to a subject a composition comprising a brain-targeting antibody or antigen-binding fragment thereof, wherein the brain-targeting antibody or antigen-binding fragment thereof is at a concentration of about 130 mg / mL to about 200 mg / mL.

[0013]

[0013] In one aspect, the present disclosure provides a method for delaying clinical deterioration in a patient diagnosed with early or mild-to-moderate Alzheimer's disease (AD), the method comprising subcutaneously administering to the subject a composition comprising a brain-targeting antibody or antigen-binding fragment thereof, wherein the brain-targeting antibody or antigen-binding fragment thereof is at a concentration of about 130 mg / mL to about 200 mg / mL.

[0014] In some embodiments, the concentration of the brain-targeting antibody or antigen-binding fragment thereof is about 140 mg / mL to about 190 mg / mL. In some embodiments, the concentration of the brain-targeting antibody or antigen-binding fragment thereof is about 150 mg / mL to about 180 mg / mL. In some embodiments, the concentration of the brain-targeting antibody or antigen-binding fragment thereof is about 150 mg / mL. In some embodiments, the concentration of the brain-targeting antibody or antigen-binding fragment thereof is about 170 mg / mL. In some embodiments, the concentration of the brain-targeting antibody or antigen-binding fragment thereof is about 180 mg / mL.

[0015] In some embodiments, the brain-targeting antibody or antigen-binding fragment thereof is administered at a dose between about 400 mg and about 7500 mg. In some embodiments, the dose of the brain-targeting antibody or antigen-binding fragment thereof is about 600 mg to about 7200 mg. In some embodiments, the dose of the brain-targeting antibody or antigen-binding fragment thereof is about 600 mg. In some embodiments, the dose of the brain-targeting antibody or antigen-binding fragment thereof is about 1200 mg. In some embodiments, the dose of the brain-targeting antibody or antigen-binding fragment thereof is about 1700 mg. In some embodiments, the dose of the brain-targeting antibody or antigen-binding fragment thereof is about 1800 mg. In some embodiments, the dose of the brain-targeting antibody or antigen-binding fragment thereof is about 2400 mg. In some embodiments, the dose of the brain-targeting antibody or antigen-binding fragment thereof is about 3400 mg. In some embodiments, the dose of the brain-targeting antibody or antigen-binding fragment thereof is about 3600 mg. In some embodiments, the dose of the brain-targeting antibody or antigen-binding fragment thereof is about 4320 mg. In some embodiments, the dose of the brain-targeting antibody or antigen-binding fragment thereof is about 5760 mg. In some embodiments, the dose of the brain-targeting antibody or antigen-binding fragment thereof is about 6800 mg. In some embodiments, the dose of the brain-targeting antibody or antigen-binding fragment thereof is about 7200 mg.

[0016] In some embodiments, the brain-targeting antibody or antigen-binding fragment thereof is administered in an injection volume of about 4 mg / mL to about 60 mL. In some embodiments, the injection volume is about 10 mL to about 40 mL. In some embodiments, the injection volume is about 4 mL. In some embodiments, the injection volume is about 8 mL. In some embodiments, the injection volume is about 10 mL. In some embodiments, the injection volume is about 12 mL. In some embodiments, the injection volume is about 16 mL. In some embodiments, the injection volume is about 20 mL. In some embodiments, the injection volume is about 24 mL. In some embodiments, the injection volume is about 32 mL.

[0017] In some embodiments, the injection volume is about 40 mL.

[0018] In some embodiments, the brain-targeting antibody or antigen-binding fragment thereof is administered at a flow rate of about 1 mL / min to about 5 mL / min. In some embodiments, the flow rate is about 2 mL / min to about 4 mL / min. In some embodiments, the flow rate is about 2 mL / min. In some embodiments, the flow rate is about 4 mL / min.

[0019] In some embodiments, the method further comprises administering to the subject a permeation enhancer. In some embodiments, the permeation enhancer is a hyaluronidase (e.g., Amphadase®, Hydase®, Hylenex®, and Vitrase®). In some embodiments, the permeation enhancer is a recombinant human hyaluronidase. In some embodiments, the recombinant human hyaluronidase is a human soluble PH20 hyaluronidase glycoprotein, such as rHuPH20. In some embodiments, the brain-targeting antibody or antigen-binding fragment thereof and the permeation enhancer are administered simultaneously. In some embodiments, the brain-targeting antibody or antigen-binding fragment thereof and the permeation enhancer are administered sequentially. In some embodiments, the brain-targeting antibody or antigen-binding fragment thereof and the permeation enhancer are in the same composition. In some embodiments, the brain-targeting antibody or antigen-binding fragment thereof and the permeation enhancer are in separate compositions.

[0020] In some embodiments, the permeation enhancer is at a concentration of about 300 U / mL to about 2200 U / mL. In some embodiments, the permeation enhancer is at a concentration of about 500 U / mL to about 2000 U / mL. In some embodiments, the permeation enhancer is at a concentration of about 500 U / mL. In some embodiments, the permeation enhancer is at a concentration of about 1000 U / mL. In some embodiments, the permeation enhancer is at a concentration of about 2000 U / mL.

[0021] In some embodiments, the hyaluronidase is at a concentration of about 300 U / mL to about 2200 U / mL. In some embodiments, the hyaluronidase is at a concentration of about 500 U / mL to about 2000 U / mL. In some embodiments, the hyaluronidase is at a concentration of about 500 U / mL. In some embodiments, the hyaluronidase is at a concentration of about 1000 U / mL. In some embodiments, the hyaluronidase is at a concentration of about 2000 U / mL.

[0022] In some embodiments, the recombinant human hyaluronidase is at a concentration of about 300 U / mL to about 2200 U / mL. In some embodiments, the recombinant human hyaluronidase is at a concentration of about 500 U / mL to about 2000 U / mL. In some embodiments, the recombinant human hyaluronidase is at a concentration of about 500 U / mL. In some embodiments, the recombinant human hyaluronidase is at a concentration of about 1000 U / mL. In some embodiments, the recombinant human hyaluronidase is at a concentration of about 2000 U / mL.

[0023] In some embodiments, the composition is administered in the abdominal quadrant. In some embodiments, the composition is administered as one or more doses.

[0024]

[0023] In some embodiments, the Alzheimer's disease is autosomal dominant Alzheimer's disease. In some embodiments, the autosomal dominant Alzheimer's disease is prodromal, mild, moderate, or mild to moderate. In some embodiments, the autosomal dominant Alzheimer's disease is mild to moderate. In some embodiments, the Alzheimer's disease is sporadic AD. In some embodiments, the Alzheimer's disease is early or mild AD.

[0025]

[0024] In some embodiments, the brain-targeting antibody is a humanized monoclonal IgG4 antibody. In some embodiments, the brain-targeting antibody is an anti-amyloid beta antibody. In some embodiments, the anti-amyloid beta antibody or antigen-binding fragment thereof comprises: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:1; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:2; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:3; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:4; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO:5; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO:6. In some embodiments, the anti-amyloid beta antibody or antigen-binding fragment thereof comprises a VH domain comprising the amino acid sequence of SEQ ID NO:7. In some embodiments, the anti-amyloid beta antibody or antigen-binding fragment thereof comprises a VL domain comprising the amino acid sequence of SEQ ID NO:8. In some embodiments, the anti-amyloid beta antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO:9. In some embodiments, the anti-amyloid beta antibody comprises a light chain comprising the amino acid sequence of SEQ ID NO: 10. In some embodiments, the anti-amyloid beta antibody is crenezumab.

[0026]

[0025] In some embodiments, the subject is a human.

[0027] In some embodiments, the disclosure provides a method for treating Alzheimer's disease in a subject, the method comprising subcutaneously administering to the subject a first dose and a second dose, where (a) the first dose comprises about 1700 mg of a brain-targeting antibody or antigen-binding fragment thereof and is administered in an injection volume of 10 mL at a flow rate of about 2 mL / min; and (b) the second dose comprises about 3400 mg of a brain-targeting antibody or antigen-binding fragment thereof and is administered in an injection volume of 20 mL at a flow rate of about 2 mL / min. In some embodiments, the first dose is administered on day 1 and the second dose is administered on day 15.

[0028] In some embodiments, the disclosure provides a method for treating Alzheimer's disease in a subject, the method comprising subcutaneously administering to the subject a first dose and a second dose; (a) a first dose comprises about 3400 mg of a brain-targeting antibody or antigen-binding fragment thereof and is administered in an injection volume of 20 mL at a flow rate of about 4 mL / min; said first dose is co-administered with hyaluronidase at a dose of about 2000 U / mL; (b) a second dose comprising about 6800 mg of a brain-targeting antibody or antigen-binding fragment thereof administered in an injection volume of 40 mL at a flow rate of about 4 mL / min; said second dose is co-administered with hyaluronidase at a dose of about 1000 U / mL. In some embodiments, the first dose and human hyaluronidase (at a dose of about 2000 U / mL) are administered on day 1 and the second dose and hyaluronidase (at a dose of about 1000 U / mL) are administered on day 15.

[0029] In some embodiments, the disclosure provides a method for treating Alzheimer's disease in a subject, the method comprising subcutaneously administering to the subject a first dose and a second dose; (a) a first dose comprises about 3400 mg of a brain-targeting antibody or antigen-binding fragment thereof, administered in an injection volume of 20 mL at a flow rate of about 4 mL / min; said first dose is co-administered with recombinant human hyaluronidase at a dose of about 2000 U / mL; (b) a second dose comprising about 6800 mg of a brain-targeting antibody or antigen-binding fragment thereof administered in an injection volume of 40 mL at a flow rate of about 4 mL / min; said second dose is co-administered with recombinant human hyaluronidase at a dose of about 1000 U / mL. In some embodiments, the first dose and recombinant human hyaluronidase (at a dose of about 2000 U / mL) are administered on day 1 and the second dose and recombinant human hyaluronidase (at a dose of about 1000 U / mL) are administered on day 15.

[0030] In some embodiments, the disclosure provides a method for treating Alzheimer's disease in a subject, the method comprising subcutaneously administering to the subject a first dose and a second dose, where (a) the first dose comprises about 1700 mg of a brain-targeting antibody or antigen-binding fragment thereof and is administered in an injection volume of 10 mL at a flow rate of about 4 mL / min; and (b) the second dose comprises about 3400 mg of a brain-targeting antibody or antigen-binding fragment thereof and is administered in an injection volume of 40 mL at a flow rate of about 4 mL / min. In some embodiments, the first dose is administered on day 1 and the second dose is administered on day 15.

[0031] In some embodiments, the disclosure provides a method for treating Alzheimer's disease in a subject, the method comprising subcutaneously administering to the subject a first dose and a second dose; (a) the first dose comprises about 3400 mg of a brain-targeting antibody or antigen-binding fragment thereof and is administered in an injection volume of 20 mL at a flow rate of about 4 mL / min; (b) a second dose comprising about 6800 mg of a brain-targeting antibody or antigen-binding fragment thereof administered in an injection volume of 40 mL at a flow rate of about 4 mL / min; said second dose is co-administered with hyaluronidase at a dose of about 500 U / mL. In some embodiments, the first dose is administered on day 1 and the second dose and hyaluronidase are administered on day 15.

[0032] In some embodiments, the disclosure provides a method for treating Alzheimer's disease in a subject, the method comprising subcutaneously administering to the subject a first dose and a second dose; (a) the first dose comprises about 3400 mg of a brain-targeting antibody or antigen-binding fragment thereof and is administered in an injection volume of 20 mL at a flow rate of about 4 mL / min; (b) a second dose comprising about 6800 mg of a brain-targeting antibody or antigen-binding fragment thereof administered in an injection volume of 40 mL at a flow rate of about 4 mL / min; said second dose is co-administered with recombinant human hyaluronidase at a dose of about 500 U / mL. In some embodiments, the first dose is administered on day 1 and the second dose and recombinant human hyaluronidase are administered on day 15.

[0033] In some embodiments, the disclosure provides a method for treating Alzheimer's disease in a subject, the method comprising subcutaneously administering to the subject a first dose and a second dose; (a) a first dose comprises about 3400 mg of a brain-targeting antibody or antigen-binding fragment thereof and is administered in an injection volume of 20 mL at a flow rate of about 4 mL / min; said first dose is co-administered with hyaluronidase at a dose of about 2000 U / mL; (b) a second dose comprising about 6800 mg of a brain-targeting antibody or antigen-binding fragment thereof administered in an injection volume of 40 mL at a flow rate of about 4 mL / min; said second dose is co-administered with hyaluronidase at a dose of about 500 U / mL. In some embodiments, the first dose and hyaluronidase (at a dose of about 2000 U / mL) are administered on day 1 and the second dose and hyaluronidase (at a dose of about 500 U / mL) are administered on day 15.

[0034] In some embodiments, the disclosure provides a method for treating Alzheimer's disease in a subject, the method comprising subcutaneously administering to the subject a first dose and a second dose; (a) a first dose comprises about 3400 mg of a brain-targeting antibody or antigen-binding fragment thereof, administered in an injection volume of 20 mL at a flow rate of about 4 mL / min; said first dose is co-administered with recombinant human hyaluronidase at a dose of about 2000 U / mL; (b) a second dose comprising about 6800 mg of a brain-targeting antibody or antigen-binding fragment thereof administered in an injection volume of 40 mL at a flow rate of about 4 mL / min; said second dose is co-administered with recombinant human hyaluronidase at a dose of about 500 U / mL. In some embodiments, the first dose and recombinant human hyaluronidase (at a dose of about 2000 U / mL) are administered on day 1 and the second dose and recombinant human hyaluronidase (at a dose of about 500 U / mL) are administered on day 15.

[0035]

[0034] In some embodiments, the disclosure provides a method for treating Alzheimer's disease in a subject, the method comprising subcutaneously administering to the subject a composition comprising about 6,800 mg of a brain-targeting antibody or antigen-binding fragment thereof administered at a flow rate of about 4 mL / min in an injection volume of about 40 mL and recombinant human hyaluronidase at a dose of about 500 U / mL.

[0036]

[0035] In some embodiments, the brain-targeting antibody or antigen-binding fragment thereof is an anti-amyloid beta antibody or antigen-binding fragment thereof. In some embodiments, the anti-amyloid beta antibody or antigen-binding fragment thereof comprises: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:1; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:2; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:3; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:4; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO:5; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO:6. In some embodiments, the anti-amyloid beta antibody or antigen-binding fragment thereof comprises a VH domain comprising the amino acid sequence of SEQ ID NO:7. In some embodiments, the anti-amyloid beta antibody or antigen-binding fragment thereof comprises a VL domain comprising the amino acid sequence of SEQ ID NO:8. In some embodiments, the anti-amyloid beta antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO:9. In some embodiments, the anti-amyloid beta antibody comprises a light chain comprising the amino acid sequence of SEQ ID NO:10. In some embodiments, the anti-amyloid beta antibody is crenezumab.

[0037]

[0036] In some embodiments, the Alzheimer's disease is autosomal dominant Alzheimer's disease. In some embodiments, the autosomal dominant Alzheimer's disease is prodromal, mild, moderate, or mild to moderate. In some embodiments, the autosomal dominant Alzheimer's disease is mild to moderate. In some embodiments, the Alzheimer's disease is sporadic AD. In some embodiments, the Alzheimer's disease is early or mild AD.

[0038]

[0037] In one aspect, the present disclosure provides compositions suitable for administering high volumes and high doses of anti-amyloid β antibodies or antigen-binding fragments thereof. In one aspect, the present disclosure provides compositions comprising about 400 mg to about 7500 mg of anti-amyloid β antibodies or antigen-binding fragments thereof. In one aspect, the present disclosure provides compositions comprising about 600 mg to about 7200 mg of anti-amyloid β antibodies or antigen-binding fragments thereof. In some embodiments, the compositions comprise about 600 mg of anti-amyloid β antibodies or antigen-binding fragments thereof. In some embodiments, the compositions comprise about 1200 mg of anti-amyloid β antibodies or antigen-binding fragments thereof. In some embodiments, the compositions comprise about 1700 mg of anti-amyloid β antibodies or antigen-binding fragments thereof. In some embodiments, the compositions comprise about 1800 mg of anti-amyloid β antibodies or antigen-binding fragments thereof. In some embodiments, the compositions comprise about 2400 mg of anti-amyloid β antibodies or antigen-binding fragments thereof. In some embodiments, the composition comprises about 3400 mg of an anti-amyloid beta antibody or antigen-binding fragment thereof. In some embodiments, the composition comprises about 3600 mg of an anti-amyloid beta antibody or antigen-binding fragment thereof. In some embodiments, the composition comprises about 4320 mg of an anti-amyloid beta antibody or antigen-binding fragment thereof. In some embodiments, the composition comprises about 5760 mg of an anti-amyloid beta antibody or antigen-binding fragment thereof. In some embodiments, the composition comprises about 6800 mg of an anti-amyloid beta antibody or antigen-binding fragment thereof. In some embodiments, the composition comprises about 7200 mg of an anti-amyloid beta antibody or antigen-binding fragment thereof.

[0039] In some embodiments, the composition further comprises a permeation enhancer. In some embodiments, the composition further comprises a hyaluronidase (e.g., Amphadase®, Hydase®, Hylenex®, and Vitrase®). In some embodiments, the composition further comprises a recombinant human hyaluronidase. In some embodiments, the recombinant human hyaluronidase is a human soluble PH20 hyaluronidase glycoprotein, such as rHuPH20.

[0040] In some embodiments, the permeation enhancer is at about 500 U / mL to about 2000 U / mL. In some embodiments, the concentration of the permeation enhancer is about 500 U / mL. In some embodiments, the concentration of the permeation enhancer is about 1000 U / mL. In some embodiments, the concentration of the permeation enhancer is about 2000 U / mL.

[0041] In some embodiments, the hyaluronidase is at about 500 U / mL to about 2000 U / mL. In some embodiments, the concentration of hyaluronidase is about 500 U / mL. In some embodiments, the concentration of hyaluronidase is about 1000 U / mL. In some embodiments, the concentration of hyaluronidase is about 2000 U / mL.

[0042] In some embodiments, the recombinant human hyaluronidase is at about 500 U / mL to about 2000 U / mL. In some embodiments, the concentration of the recombinant human hyaluronidase is about 500 U / mL. In some embodiments, the concentration of the recombinant human hyaluronidase is about 1000 U / mL. In some embodiments, the concentration of the recombinant human hyaluronidase is about 2000 U / mL.

[0043]

[0042] In some embodiments, the disclosure provides a composition comprising about 130 mg to about 200 mg / mL of an anti-amyloid β antibody or antigen-binding fragment thereof.

[0044]

[0043] In some embodiments, the concentration of the anti-amyloid β antibody or antigen-binding fragment thereof is about 140 mg / mL to about 190 mg / mL. In some embodiments, the concentration of the anti-amyloid β antibody or antigen-binding fragment thereof is about 150 mg / mL to about 180 mg / mL. In some embodiments, the concentration of the anti-amyloid β antibody or antigen-binding fragment thereof is about 150 mg / mL. In some embodiments, the concentration of the anti-amyloid β antibody or antigen-binding fragment thereof is about 170 mg / mL. In some embodiments, the concentration of the anti-amyloid β antibody or antigen-binding fragment thereof is about 180 mg / mL.

[0045]

[0044] In some embodiments, the composition is suitable for administering the anti-amyloid β antibody or antigen-binding fragment thereof in an injection volume of about 4 mL to about 60 mL. In some embodiments, the injection volume is about 10 mL to about 40 mL. In some embodiments, the injection volume is about 4 mL. In some embodiments, the injection volume is about 8 mL. In some embodiments, the injection volume is about 10 mL. In some embodiments, the injection volume is about 12 mL. In some embodiments, the injection volume is about 16 mL. In some embodiments, the injection volume is about 20 mL. In some embodiments, the injection volume is about 24 mL. In some embodiments, the injection volume is about 32 mL. In some embodiments, the injection volume is about 40 mL.

[0046] In some embodiments, the composition is suitable for administering the anti-amyloid β antibody or antigen-binding fragment thereof at a flow rate of about 1 mL / min to about 5 mL / min. In some embodiments, the flow rate is about 2 mL / min to about 4 mL / min. In some embodiments, the flow rate is about 2 mL / min. In some embodiments, the flow rate is about 4 mL / min.

[0047]

[0046] In some embodiments, the anti-amyloid beta antibody or antigen-binding fragment thereof includes (a) HVR-H1 having the amino acid sequence of SEQ ID NO: 1; (b) HVR-H2 having the amino acid sequence of SEQ ID NO: 2; (c) HVR-H3 having the amino acid sequence of SEQ ID NO: 3; (d) HVR-L1 having the amino acid sequence of SEQ ID NO: 4; (e) HVR-L2 having the amino acid sequence of SEQ ID NO: 5; and (f) HVR-L3 having the amino acid sequence of SEQ ID NO: 6.

[0048] In some embodiments, the anti-amyloid β antibody, or antigen-binding fragment thereof, comprises a VH domain comprising the amino acid sequence of SEQ ID NO:7.

[0049] In some embodiments, the anti-amyloid beta antibody, or antigen-binding fragment thereof, comprises a VL domain comprising the amino acid sequence of SEQ ID NO: 8. In some embodiments, the anti-amyloid beta antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 9. In some embodiments, the anti-amyloid beta antibody comprises a light chain comprising the amino acid sequence of SEQ ID NO: 10. In some embodiments, the anti-amyloid beta antibody is crenezumab.

[0050] The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee. [Brief description of the drawings]

[0051] [Figure 1A] Study Design and Treatment Schema Study 1: Single Ascending Dose Study. [Figure 1B] Study Design and Treatment Schema Study 2: Multiple-dose study with or without recombinant human hyaluronidase (rHuPH20). [Diagram 2]Study 1: VAS pain scores after subcutaneous (SC) injection (all cohorts). Dur stands for duration. SC stands for subcutaneous. VAS stands for visual analog scale. VAS is measured on a scale of 0 to 100 mm. Baseline: after catheter insertion, before injection (pre-dose); 0 min dur: retrospective assessments were collected at 0 min to describe how the subject felt while receiving the injection; immediately after stopping the syringe pump, before removing the catheter; 0 min now: immediately after injection; immediately after stopping the syringe pump, before removing the catheter; t=5: 5 min after injection; t=20: 20 min after injection; t=60: 60 min after injection. Whiskers represent the highest and lowest non-outlier values, boxes represent upper and lower quartiles, and the center line is the median. Outlier data are represented above the whiskers. Outliers represent extreme values ​​in a set of values ​​that are significantly different from the others. Extreme values ​​were considered outliers if they were at least 1.5 interquartile ranges below the first quartile or at least 1.5 interquartile ranges above the third quartile. Dashed lines represent medians. [Figure 3A-3F] Study 2: VAS pain scores after SC injection for A: Cohort 2, B: Cohort 3, C: Cohort 4, D: Cohort 5 (Day 1), E: Cohort 5A+5B, and F: Cohort 6 (Day 1+15). VAS stands for visual analog scale. VAS is measured from 0 to 100 mm. Baseline: after catheter insertion, before injection (pre-dose). During the injection, a retrospective assessment was collected at 0 minutes to describe how the subject felt while receiving the injection; immediately after the syringe pump was stopped, before the catheter was removed; t=0 minutes: immediately after injection; immediately after the syringe pump was stopped, before the catheter was removed; t=5: 5 minutes after injection; t=20: 20 minutes after injection; t=60: 60 minutes after injection. [Figure 4A-4B]

[0051] Injection site erythema area in Study 2. Cohort E (20 mL crenezumab) and Cohort H (40 mL crenezumab) from Study 1 stratified by injection volume and coadministration of rHuPH20 at time points 0 minutes post-injection (A) and 60 minutes post-injection (B). Solid lines represent median values, dashed lines represent 25th and 75th percentiles. Cren represents crenezumab. rHuPH20 represents recombinant human hyaluronidase. [Figure 5A-5B]

[0052] Mean serum concentration-time profiles following SC infusion of crenezumab in A: Study 1 and B: Study 2. Study 1: Single ascending doses of SC crenezumab (600 mg to 7200 mg) in cohorts A-H. Study 2: Cohort 2: Infusion 1, 1700 mg crenezumab (10 mL at 2 mL / min) (SC); Infusion 2, 3400 mg crenezumab (20 mL at 2 mL / min) (SC). Cohort 3: Infusion 1, 3400 mg crenezumab + 2000 U / mL rHuPH20 (20 mL at 4 mL / min) (SC); Infusion 2, 6800 mg crenezumab + 1000 U / mL rHuPH20 (40 mL at 4 mL / min) (SC). Cohort 4: infusion 1, 1700 mg crenezumab (10 mL at 4 mL / min) (SC); infusion 2, 3400 mg crenezumab (20 mL at 4 mL / min) (SC). Cohort 5A: infusion 1, 3400 mg crenezumab (20 mL at 4 mL / min) (SC); infusion 2, 6800 mg crenezumab + 500 U / mL rHuPH20 (40 mL at 4 mL / min) (SC). Cohort 5B: infusion 1, 3400 mg crenezumab + 2000 U / mL rHuPH20 (20 mL at 4 mL / min) (SC); infusion 2, 6800 mg crenezumab + 500 U / mL rHuPH20 (40 mL at 4 mL / min) (SC). Study 2 profile is the day 15 dose in cohorts 2-5, all of whom were dosed on day 1 and did not wash out by day 15. rHuPH20 stands for recombinant human hyaluronidase. SC stands for subcutaneous. [Figure 6]

[0053] Study 1: Whisker boxes for Verbal Descriptor Scale (VDS) data for all participants. Dur stands for duration. VDS stands for Verbal Descriptor Scale. The scale used for the VDS is as follows: 1=no pain, 2=very mild, 3=mild, 4=not very severe, 5=fairly severe, 6=very severe, 7=unbearable. The whiskers represent the highest and lowest non-outlier values, the boxes represent the upper and lower quartiles, and the center line is the median. Outlier data are represented above the whiskers. Outliers represent extreme values ​​that are significantly different from the other values ​​in a set of values. Extreme values ​​were considered outliers if they were at least 1.5 interquartile ranges below the first quartile or at least 1.5 interquartile ranges above the third quartile. The dashed line represents the median. [Figure 7A-7F]

[0054] Study 2: Box plots of verbal description scale (VDS) data for A: Cohort 2, B: Cohort 3, C: Cohort 4, D: Cohort 5 (day 1), E: Cohort 5A+5B, and F: Cohort 6 (day 1+15). Dur stands for duration. VDS stands for verbal description scale. The scale used for VDS is as follows: 1=no pain, 2=very mild, 3=mild, 4=not very severe, 5=very severe, 6=very severe, 7=unbearable. VDS was assessed only at baseline and t=0. [Figure 8]

[0055] Distribution of tissue backpressure following placebo injection (Cohort 6, Study 2). rHuPH20 stands for recombinant human hyaluronidase. Tissue backpressure is measured in psi. [Figure 9A-9B]

[0056] Visual predictive check (VPC) of the final model. A: Prediction correction visual predictive check of the crenezumab population PK model stratified by study and route of administration on a linear scale. B: Prediction correction visual predictive check of the crenezumab population PK model stratified by study and route of administration on a logarithmic scale. IV stands for intravenous. PK stands for pharmacokinetics. SC stands for subcutaneous. Open circles show observed crenezumab concentrations versus time. Lines represent the median, 5th, and 95th percentiles of observed values. Red and blue shaded areas represent 95% confidence intervals for the median, 5th, and 95th percentiles predicted by the model. [Figure 10]

[0057] Individual estimates of crenezumab SC bioavailability from population PK modeling by study, dose (Study 1) or cohort (Study 2). Medians are indicated by lines. PK stands for pharmacokinetics. rHuPH20 stands for recombinant human hyaluronidase. SC stands for subcutaneous. [Figure 11]

[0058] Demographic and baseline characteristics for Study 1 (single ascending dose study) and Study 2 (multiple dose-rHuPH20 study). BMI stands for body mass index. rHuPH20 stands for recombinant human hyaluronidase. SC stands for subcutaneous. SD stands for standard deviation. [Figure 12]

[0059] Summary table of Local Injection Site Symptom Assessment (LISSA) for Study 1 (Single Ascending Dose Study) and Study 2 (Multiple Dose-rHuPH20 Study). C represents crenezumab injection site. Inj represents infusion. IV represents intravenous. P represents placebo injection. R represents reference placebo injection. rHuPH20 represents recombinant human hyaluronidase. SC represents subcutaneous. T represents study placebo injection. a represents induration and swelling, which were the most common "other" injection site reactions. Tenderness, red bumps / redness bumps, edema, and pain were also reported multiple times but to a much lesser extent. All other reactions (including hypersensitivity, papule, stinging, wheal formation, and intact blisters) were reported only once each. b represents that not all participants were assessable for these reactions at a given time point. Data represent the sum of injection site reaction events captured at different times after injection. [Figure 13]

[0060] Summary tables of treatment-emergent adverse events in Study 1 (single ascending dose study) and Study 2 (multiple dose-rHuPH20 study). AE stands for adverse event. IV stands for intravenous. rHuPH20 stands for recombinant human hyaluronidase. SAE stands for serious adverse event. SC stands for subcutaneous. a stands for infusion 1 only. Participants in cohort 5A received crenezumab alone and participants in cohort 5B received crenezumab + rHuPH20. b stands for infusion 2 only. All participants received crenezumab + rHuPH20. [Figure 14]

[0061] Table of parameter estimates from the crenezumab population PK model. a represents SD of the logistic distribution. CV represents the coefficient of variation. IIV represents interindividual variability. RSE represents relative standard error. SHR represents shrinkage. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0052]

[0062] The present disclosure provides compositions suitable for subcutaneous administration comprising high-volume and high-dose brain-targeting antibodies or antigen-binding fragments thereof, and methods of use thereof for treating cognitive disorders, including Alzheimer's disease.

[0053] definition

[0063] The practice of the methods disclosed herein and the preparation and use of the compositions will employ common techniques within the skill of the art in molecular biology, biochemistry, chromatin structure and analysis, computational chemistry, cell culture, recombinant DNA and related fields, unless otherwise indicated. These techniques are fully described in the literature. See, for example, Sambrook et al. MOLECULAR CLONING: A LABORATORY MANUAL, Fourth edition, Cold Spring Harbor Laboratory Press, 2014; Ausubel et al., CURRENT PROTOCOLS IN MOLECULAR BIOLOGY, John Wiley & Sons, New York, 2012; the series METHODS IN ENZYMOLOGY, Academic Press, San Diego; Wolffe, Murphy et al. JANEWAY'S IMMUNOBIOLOGY, Tenth Edition, WW Norton & Company, 2022.

[0054]

[0064] The term "herein" means the entire specification.

[0055]

[0065] Unless otherwise defined herein, scientific and technical terms used in this application shall have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Generally, the nomenclature used in connection with the compounds, compositions and methods described herein is one that is well known and commonly used in the art.

[0056]

[0066] It should be understood that any of the embodiments described herein, including those described in different aspects of the disclosure and in different parts of the specification (including embodiments described only in the examples), can be combined with one or more other embodiments disclosed herein, unless expressly stated to the contrary or inappropriate. Combinations of embodiments are not limited to the specific combinations claimed by multiple dependent claims.

[0057]

[0067] Any publications, patents, and published patent applications mentioned herein are specifically incorporated herein by reference. In case of conflict, the present specification, including its specific definitions, will control.

[0058]

[0068] Throughout this specification, the term "comprise" or variations such as "comprises" or "comprising," which are synonymous with "including," "containing," or "characterized by," are inclusive or open-ended and do not exclude additional, unrepresented elements or method steps.

[0059]

[0069] The term "consisting of" excludes any element, step, or ingredient not specifically recited.

[0060]

[0070] The term "consisting essentially of" limits the disclosure to the particular materials or steps, and those that do not materially affect the basic and novel characteristics of the disclosure.

[0061]

[0071] Throughout this specification, when a composition is described as having, including, or comprising a particular component (or a variation thereof), it is contemplated that the composition may consist essentially of or consist of the recited component. Similarly, when a method or process is described as having, including, or comprising a particular process step, the process may consist essentially of or consist of the recited process step. Furthermore, it should be understood that the order of steps or order of performing certain actions is immaterial so long as the compositions and methods described herein are operable. Moreover, two or more steps or actions may be performed simultaneously.

[0062]

[0072] The term "eg" or "for example" followed by one or more examples is not meant to be exclusive or limiting.

[0063]

[0073] The articles "a" and "an" are used herein to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, "an element" means one element or more than one element.

[0064]

[0074] As used herein, the term "about" to modify the quantity of a composition component, parameter, calculation, or measurement used in the disclosed method refers to variations in quantity that may occur, for example, due to common measuring and liquid handling procedures used to make isolated polypeptides or pharmaceutical compositions in the real world; due to inadvertent errors in these procedures; due to differences in the manufacture, source, or purity of the components used to make the composition or carry out the method; without substantially affecting the chemical or physical attributes of the disclosed composition or method. Such variations may be within a range of magnitude, typically within 10%, more typically within 5%, of a given value or range. The term "about" also encompasses amounts that vary due to different equilibrium conditions of a composition resulting from a particular initial mixture. Whether or not modified by the term "about," a paragraph includes its equivalent of the quantity. Reference herein to a value or parameter "about" includes (describes) an embodiment for the value or parameter itself. For example, a description that refers to "about X" includes the description of "X." A numerical range includes the numerical values ​​defining the range.

[0065]

[0075] As used herein, the term "or" should be understood to mean "and / or" unless the context clearly indicates otherwise.

[0066] Notwithstanding that the numerical ranges and parameters setting forth the broad scope of the present disclosure are approximations, the numerical values ​​set forth in the specific examples are reported as precisely as possible. However, any numerical value inherently contains certain errors necessarily resulting from the standard deviation found in their respective testing measurements. Moreover, all ranges disclosed herein should be understood to encompass all subranges contained therein. For example, a range described as "1 to 10" should be considered to include all subranges between the minimum value of 1 and the maximum value of 10, inclusive; i.e., all subranges beginning with a minimum value equal to or greater than 1, e.g., 1 to 6.1, and all subranges ending with a maximum value equal to or less than 10, e.g., 5.5 to 10. The disclosure of a range should also be considered as a disclosure of the endpoints of that range.

[0067]

[0077] Exemplary methods and materials are described below, although methods and materials similar or equivalent to those described herein can also be used in the practice or testing of this application. The materials, methods, and examples are illustrative only and not intended to be limiting.

[0068]

[0078] It should be understood that any of the embodiments described herein, including those described in different aspects of the disclosure and in different parts of the specification (including embodiments described only in the examples), can be combined with one or more other embodiments of the disclosure, unless expressly stated to the contrary or inappropriately. Combinations of embodiments are not limited to the specific combinations claimed by multiple dependent claims.

[0069]

[0079] "Administering" a substance, compound, or agent to a subject or "administration of" a substance, compound, or agent to a subject refers to contacting the substance, compound, or agent with the subject or with the subject's cells, tissues, organs, or bodily fluids. Such administration can be performed using one of a variety of methods known to those of skill in the art. For example, the compound or agent can be administered parenterally, such as subcutaneously. Administration can also be performed, for example, once, multiple times, and / or over one or more extended periods of time. In some embodiments, administration includes both direct administration, including self-administration, and indirect administration, including the act of prescribing a drug. For example, as used herein, a physician who instructs a subject to self-administer a drug or to have another person administer a drug, and / or who provides a prescription for a drug to a subject, is administering the drug to a subject.

[0070]

[0080] As used herein, the term "antibody" or "Ab" refers to an immunoglobulin molecule (e.g., a complete antibody, an antibody fragment, or a modified antibody) that can recognize and bind to a specific target or antigen, such as a carbohydrate, a polynucleotide, a lipid, a polypeptide, etc., located in the variable region of the immunoglobulin molecule through at least one antigen recognition site. As used herein, the term "antibody" can include any type of antibody, including, but not limited to, monoclonal, polyclonal, human, engineered antibodies (including humanized, fully human, chimeric, single chain, artificially selected, CDR-bearing, full-length, or intact antibodies, etc.) that specifically bind to a given antigen. In some embodiments, "antibody" and / or "immunoglobulin" (Ig) refers to a polypeptide that includes at least two heavy (H) chains (about 50-70 kDa) and two light (L) chains (about 25 kDa), optionally interconnected by disulfide bonds. There are two types of light chains: lambda and kappa. In humans, the lambda and kappa light chains are similar, but only one type is present in each antibody. Heavy chains are classified as mu, delta, gamma, alpha, or epsilon, and define the antibody's isotype as IgM, IgD, IgG, IgA, and IgE, respectively. See generally, Fundamental Immunology Ch. 7 (Paul, W., ed., 2nd ed. Raven Press, NY (1989)), which is incorporated herein by reference in its entirety.

[0071]

[0081] The terms "subject" and "patient" are used interchangeably herein and refer to mammals, including but not limited to humans and non-human animals. These terms include mammals, such as humans, and primates (e.g., monkeys). In some embodiments, the subject is a human. Thus, the term "subject" or "patient" as used herein refers to any mammalian patient or subject to which the compositions of the present disclosure can be administered.

[0072]

[0082] "Treatment" (and grammatical variations thereof, such as "treat" or "treating") refers to a clinical intervention that attempts to alter the natural course of the individual being treated, and may be performed during the course of clinical pathology. Desirable effects of treatment include, but are not limited to, alleviation or amelioration of one or more symptoms, diminishment or delay in the appearance or worsening of any direct or indirect pathological consequence of the disease, reduction in the rate of disease progression, and amelioration or palliation of the disease state. In some embodiments, the antibodies are used to delay the onset of the disease or slow the progression of the disease.

[0073]

[0083] The terms "therapeutically effective amount" and "effective amount" are used interchangeably herein and refer to an amount of a therapeutic agent administered as a single agent or in combination with one or more additional agents that will relieve to some extent one or more of the symptoms of the condition being treated. In some embodiments, a therapeutically effective amount is an amount sufficient to produce an effective or desired clinical result. In the context of treating a condition (e.g., Alzheimer's disease), a therapeutically effective amount refers to an amount that has at least one effect of mitigating, ameliorating, stabilizing, reversing, preventing, slowing, or delaying the progression of the condition (and / or symptoms associated therewith), such as modifying the progression of AD, particularly mild to moderate AD, and / or alleviating and / or preventing one or more symptoms of AD. In some embodiments, an effective amount is used to reduce the rate of memory decline. Effective amounts that can be used in the present disclosure vary depending on the mode of administration, the age, weight, and general health of the subject. Appropriate amounts and dosing regimens can be determined using routine skill in the art.

[0074]

[0084] The term "therapeutic agent" refers to any agent used to treat a disease, including, but not limited to, agents that treat the symptoms of a disease.

[0075]

[0085] As used herein, "delaying" or "slowing" disease progression refers to preventing, postponing, hindering, delaying, stabilizing, and / or postponing the onset of the disease so as to modify the progression of AD, particularly mild to moderate AD. Such delays can be of varying lengths of time, depending on the disease and / or medical history of the individual being treated.

[0076]

[0086] "Symptom" as used herein refers to any phenomenon or sensation experienced by a subject that deviates from normal function, sensation, or structure.

[0077]

[0087] The term "monoclonal antibody" as used herein refers to an antibody obtained from a population of substantially homogeneous antibodies, i.e., the individual antibodies comprising the population are identical, except for possible naturally occurring variants that may be present in minor amounts. Monoclonal antibodies are highly specific and directed against a single antigen. Furthermore, in contrast to polyclonal antibody preparations, which typically contain different antibodies directed against different determinants (epitopes), each monoclonal antibody is directed against a single determinant on the antigen.

[0078]

[0088] The monoclonal antibodies herein include: Specifically included are "chimeric" antibodies (immunoglobulins) in which a portion of the heavy and / or light chain is identical to or homologous to corresponding sequences in antibodies from a particular species or belonging to a particular antibody class or subclass, while the remainder of one or more chains is identical to or homologous to corresponding sequences in antibodies from another species or belonging to another antibody class or subclass, as well as fragments of such antibodies so long as they exhibit the desired biological activity (U.S. Pat. No. 4,816,567; and Morrison et al., Proc. Natl. Acad. Sci. USA 81:6851-6855 (1984)).

[0079]

[0089] The "class" of an antibody refers to the type of constant domain or constant region that its heavy chain possesses. There are five major classes of antibodies: IgA, IgD, IgE, IgG, and IgM, and several of these can be further divided into subclasses (or "isotypes"), e.g., IgG1, IgG2, IgG3, IgG4, IgAl, and IgA2. The heavy chain constant domains that correspond to the various classes of immunoglobulins are called α, δ, ε, γ, and μ, respectively.

[0080]

[0090] "Humanized" forms of non-human (e.g., murine) antibodies are chimeric antibodies that contain minimal sequence derived from non-human immunoglobulin. In most cases, humanized antibodies are human immunoglobulins (recipient antibody) in which residues from a hypervariable region of the recipient are replaced by residues from a hypervariable region of a non-human species (donor antibody), such as mouse, rat, rabbit, or non-human primate, having the desired specificity, affinity, and capacity. In some cases, framework region (FR) residues of the human immunoglobulin are replaced by corresponding non-human residues. Furthermore, humanized antibodies may comprise residues that are not found in the recipient antibody or in the donor antibody. These modifications are made to further refine antibody performance. In general, humanized antibodies will comprise substantially all of at least one, and typically two, variable domains, with all or substantially all of the hypervariable loops corresponding to those of a non-human immunoglobulin, and all or substantially all of the FRs being those of human immunoglobulin sequences. A humanized antibody optionally also comprises at least a portion of an immunoglobulin constant region (Fc), typically that of a human immunoglobulin. For further details, see, e.g., Jones et al., Nature 321:522-525 (1986); Riechmann et al., Nature 332:323-329 (1988); and Presta, Curr. Op. Struct. Biol. 2:593-596 (1992). See also the following reviews and references cited within these publications: Vaswani and Hamilton, Ann. Allergy, Asthma & Immunol. 1:105-115 (1998); Harris, Biochem. Soc. Transactions 23:1035-1038 (1995); Hurle and Gross, Curr. Op. Biotech. 5:428-433 (1994).

[0081]

[0091] A "human antibody" is one that contains an amino acid sequence that corresponds to that of an antibody produced by a human or a human cell, and / or that contains amino acids that correspond to the amino acid sequence of an antibody derived from a non-human source that utilizes the human antibody repertoire or other human antibody-encoding sequences (e.g., produced using any of the techniques for producing human antibodies as disclosed herein). Such techniques include screening combinatorial libraries of human origin, such as phage display (see, e.g., Marks et al., J. Mol. Biol., 222:581-597 (1991) and Hoogenboom et al., Nucl. Acids Res., 19:4133-4137 (1991)); the use of human myeloma and mouse-human heteromyeloma cell lines for the production of human monoclonal antibodies (see, e.g., Kozbor J. Immunol., 133:3001 (1984); Brodeur et al., Monoclonal Antibody Production Techniques and Applications, pp. 55-93 (Marcel Dekker, Inc., New York, 1987); and Boerner et al., J. Immunol., 1999, 11:111-112 (1999)). al., J. Immunol., 147:86 (1991); and the generation of monoclonal antibodies in transgenic animals (e.g., mice) capable of producing a full repertoire of human antibodies in the absence of endogenous immunoglobulin production (see, e.g., Jakobovits et al., Proc. Natl. Acad. Sci USA, 90:2551 (1993); Jakobovits et al., Nature, 362:255 (1993); Bruggermann et al., Year in Immunol., 7:33 (1993)). This definition of human antibody specifically excludes humanized antibodies which contain antigen-binding residues derived from a non-human animal.

[0082]

[0092] An "isolated" antibody is one that has been identified and separated and / or recovered from components of its natural environment. Contaminant components of its natural environment are substances that may interfere with diagnostic and therapeutic uses of the antibody, and these may include enzymes, hormones, and other proteinaceous or non-proteinaceous solutes. In some embodiments, the antibody is purified to greater than 95% or greater than 99% purity, for example, as determined by electrophoresis (e.g., SDS-PAGE, isoelectric focusing (IEF), capillary electrophoresis) or chromatography (e.g., ion exchange or reverse phase HPLC). For a review of methods for assessment of antibody purity, see, e.g., Flatman et al., J. Chromatogr. B 848:79-87 (2007).

[0083]

[0093] The term "variable region" or "variable domain" refers to the domain of an antibody heavy or light chain that is involved in binding the antibody to an antigen. The heavy and light chain variable domains (VH and VL, respectively) of natural antibodies generally have a similar structure, with each domain containing four conserved framework regions (FR) and three hypervariable regions (HVR). (See, e.g., Kindt et al. Kuby Immunology, 6th ed., WH Freeman and Co., p. 91 (2007)). A single VH or VL domain may be sufficient to confer antigen-binding specificity. Furthermore, antibodies that bind to a particular antigen may be isolated using a VH or VL domain from an antibody that binds the antigen, and a library of complementary VL or VH domains, respectively, may be screened. See, e.g., Portolano et al., J. Immunol. 150:880-887 (1993); Clarkson et al., Nature 352:624-628 (1991).

[0084]

[0094] As used herein, the term "hypervariable region", "HVR" or "HV" refers to the region of an antibody variable domain that is sequence hypervariable and / or forms structurally defined loops. Generally, an antibody contains six hypervariable regions, three in VH (HI, H2, H3) and three in VL (LI, L2, L3). Several hypervariable region descriptive methods are in use and are encompassed herein. Kabat complementarity determining regions (CDRs) are based on sequence variability and are the most commonly used (Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md. (1991)). Chothia instead refers to the location of the structural loops (Chothia and Lesk J. Mol. Biol. 196:901-917 (1987)). The AbM hypervariable regions are a compromise between the Kabat CDRs and Chothia structural loops and are used by Oxford Molecular's AbM antibody modeling software. The "contact" hypervariable regions are based on an analysis of available complex crystal structures. Residues from each of these HVRs are listed in Table 1 below.

[0085]

[0095] The hypervariable regions may include "extended hypervariable regions" as follows: 24-36 or 24-34 (LI), 46-56 or 49-56 or 50-56 or 52-56 (L2), and 89-97 (L3) in VL, and 26-35 (HI), 50-65 or 49-65 (H2), and 93-102, 94-102, or 95-102 (H3) in VH. The variable domain residues are numbered according to Kabat et al., supra, for each of these definitions. TIFF2024526880000002.tif46170

[0086]

[0096] "Framework" or "FR" residues are those variable domain residues other than the hypervariable region residues as herein defined. The FR of a variable domain generally consists of four FR domains: FR1, FR2, FR3, and FR4. Thus, the HVR and FR sequences generally appear in VH (or VL) in the following sequence: FR1-H1(L1)-FR2-H2(L2)-FR3-H3(L3)-FR4.

[0087]

[0097] For purposes herein, an "acceptor human framework" is a framework that comprises the amino acid sequence of a light chain variable domain (VL) framework or a heavy chain variable domain (VH) framework derived from a human immunoglobulin framework or a human consensus framework, as defined below. An acceptor human framework "derived from" a human immunoglobulin framework or a human consensus framework may comprise its identical amino acid sequence or may contain amino acid sequence changes. In some embodiments, the number of amino acid changes is 10 or less, 9 or less, 8 or less, 7 or less, 6 or less, 5 or less, 4 or less, 3 or less, or 2 or less. In some embodiments, the VL acceptor human framework is identical in sequence to the VL human immunoglobulin framework sequence or the human consensus framework sequence.

[0088]

[0098] "Affinity" or "binding affinity" refers to the strength of the sum of non-covalent interactions between a single binding site of a molecule (e.g., an antibody) and its binding partner (e.g., an antigen). Unless otherwise indicated, as used herein, "binding affinity" refers to the intrinsic binding affinity that reflects a 1:1 interaction between members of a binding pair (e.g., an antibody and an antigen-binding arm). In general, the affinity of a molecule X for its partner Y can be represented by a dissociation constant (kd). Affinity can be measured by common methods known in the art, including those described herein, any of which can be used for purposes of the present disclosure. Specific and illustrative exemplary embodiments for measuring binding affinity are described herein.

[0089]

[0099] An "affinity matured" antibody refers to an antibody that has one or more modifications in one or more hypervariable regions (HVRs) compared to a parent antibody that does not have the modifications in that HVR, which modifications result in improved affinity of the antibody for antigen.

[0090]

[0100] The terms "anti-amyloid beta", "anti-Aβ", "anti-Abeta", "anti-amyloid beta immunoglobulin", and "antibody that binds Aβ" are used interchangeably herein and refer to an antibody that specifically binds to human Abeta (Aβ). A non-limiting example of an anti-amyloid beta antibody is crenezumab. Other non-limiting examples of anti-amyloid beta antibodies include solanezumab, bapinezumab, aducanumab, and gantenerumab. In some embodiments, the anti-amyloid beta antibody comprises: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:1; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:2; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:3; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:4; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO:5; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO:6. In some embodiments, the anti-amyloid beta antibody comprises a VH domain comprising the amino acid sequence of SEQ ID NO:7. In some embodiments, the anti-amyloid beta antibody comprises a VL domain comprising the amino acid sequence of SEQ ID NO: 8. In some embodiments, the anti-amyloid beta antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 9. In some embodiments, the anti-amyloid beta antibody comprises a light chain comprising the amino acid sequence of SEQ ID NO: 10. In some embodiments, the anti-amyloid beta antibody is an IgG antibody. In some embodiments, the anti-amyloid beta antibody is an IgG4 antibody. In some embodiments, the IgG4 antibody comprises a mutation in its constant domain such that serine 228 is replaced by proline.

[0091]

[0101] The terms "Crenezumab" and "MABT5102A" are used interchangeably herein and refer to a specific anti-amyloid beta antibody that binds to monomeric, oligomeric and fibrillar forms of Aβ and is related to CAS Registry Number 1095207. Crenezumab comprises a heavy chain comprising the amino acid sequence of SEQ ID NO:9 and a light chain comprising the amino acid sequence of SEQ ID NO:10.

[0092]

[0102] The terms "amyloid beta," "Aβ," or "β-amyloid" are used interchangeably herein and are art-recognized terms and refer to amyloid beta proteins and peptides, amyloid beta precursor protein (APP), including those produced by beta-secretase 1 cleavage, as well as modified forms, fragments, and any functional equivalents thereof. Amyloid beta, as used herein, means any fragment produced by proteolytic cleavage of APP, including Aβ. 1-38 , Aβ 1-39 , Aβ 1-40 , Aβ 1-41 , Aβ 1-42 , Aβ 1-43 The present invention also includes fragments involved in or associated with amyloid pathology, including, but not limited to,

[0093]

[0103] The structures and sequences of amyloid β peptides as disclosed herein are well known to those skilled in the art, and methods for producing said peptides or extracting them from brain and other tissues are described, for example, in Glenner and Wong, Biochem Biophys Res Comm 129, 885-890 (1984). Furthermore, amyloid β peptides are also commercially available in various forms.

[0094]

[0104] The term "specifically binds" with respect to an antibody refers to an antibody that binds to its target antigen with greater affinity than a structurally distinct antigen.

[0095]

[0105] A "human consensus framework" is a framework that represents the most commonly occurring amino acid residues in a selection of human immunoglobulin VL or VH framework sequences. Typically, the selection of human immunoglobulin VL or VH sequences is from a subgroup of variable domain sequences. Typically, the subgroup of sequences is a subgroup as found in Kabat et al. Sequences of Proteins of Immunological Interest, 5th ed., NIH Publication 91-3242, Bethesda MD (1991), vols. 1-3.

[0096] The term "early Alzheimer's disease" or "early AD" as used herein (e.g., "a patient diagnosed with early AD" or "a patient suffering from early AD") includes patients with mild cognitive impairment due to AD, such as memory deficits, and patients with AD biomarkers, e.g., amyloid positive patients.

[0097]

[0107] As used herein, the term "mild Alzheimer's disease" or "mild AD" (e.g., "a patient diagnosed with mild AD") refers to a stage of AD characterized by a Minor Mental Status Examination (MMSE) score of 20-26.

[0098]

[0108] The term "mild-to-moderate Alzheimer's disease" or "mild-to-moderate AD" as used herein encompasses both mild and moderate AD, characterized by an MMSE score of 18-26.

[0099]

[0109] As used herein, the term "moderate Alzheimer's disease" or "moderate AD" (e.g., "a patient diagnosed with moderate AD") refers to a stage of AD characterized by an MMSE score of 18-19.

[0100]

[0110] The term "amyloid-related imaging abnormality (ARIA)" as used herein refers to an adverse event that occurs during treatment. In some embodiments, the ARIA is an amyloid-related imaging abnormality-edema. In some embodiments, the ARIA is an amyloid-related imaging abnormality-hemorrhage.

[0101]

[0111] The term "amyloid-related imaging abnormalities-edema" or "ARIA-E" encompasses cerebral vasogenic edema and sulcal effusion. In some embodiments, the disclosed methods of treating Alzheimer's disease do not increase the risk of a treatment-emergent adverse event, where the adverse event is amyloid-related imaging abnormalities-edema (ARIA-E).

[0102]

[0112] The term "amyloid-related imaging abnormalities-hemorrhage" or "ARIA-H" encompasses central nervous system microhemorrhages and superficial siderosis. In some embodiments, the disclosed methods of treating Alzheimer's disease do not increase the risk of a treatment-emergent adverse event, where the adverse event is amyloid-related imaging abnormalities-edema (ARIA-E).

[0103]

[0113] The term "cerebral vasogenic edema" as used herein refers to the excessive accumulation of intravascular fluid or protein in the intracellular or extracellular space of the brain. Cerebral vasogenic edema can be detected, for example, by brain MRI, including but not limited to FLAIR MRI, and may be asymptomatic ("asymptomatic vasogenic edema") or may be accompanied by neurological symptoms such as confusion, dizziness, vomiting, and lethargy ("symptomatic vasogenic edema") (see Sperling et al. Alzheimer's & Dementia, 7:367, 2011).

[0104]

[0114] The term "sulcal effusion" as used herein refers to the effusion of fluid in the creases or grooves of the brain. Sulcal effusion can be detected, for example, by brain MRI, including but not limited to FLAIR MRI. See Sperling et al. Alzheimer's & Dementia, 7:367, 2011.

[0105]

[0115] The term "superficial siderosis of the central nervous system" as used herein refers to bleeding into the subarachnoid space of the brain, detectable, for example, by brain MRI, including but not limited to T2*-weighted GRE MRI. Symptoms indicative of superficial siderosis of the central nervous system include sensorineural hearing loss, cerebellar ataxia, and pyramidal signs. See Kumara-N, Am J Neuroradiol.31:5,2010.

[0106]

[0116] The term "progression" as used herein refers to the worsening of a disease over time. The "progression rate" or "rate of progression" of a disease refers to how fast or slow the disease progresses over time in patients diagnosed with the disease. The rate of progression of a disease can be represented by measurable changes in certain characteristics of the disease over time. If the pathology of a patient carrying a certain genetic trait progresses faster than that of a patient not carrying such a genetic trait, it is said that there is or is likely to be an "increased rate of progression". On the other hand, if the disease progression of a patient responding to a therapy slows down after treatment compared to the pathology before treatment or other patients not receiving treatment, it is said that there is or is likely to be a "decreased rate of progression".

[0107]

[0117] The term "effector function" as used herein refers to the biological activity attributable to the Fc region of an antibody and varies with antibody isotype. Examples of antibody effector functions include: C1q binding and complement-dependent cytotoxicity (CDC); Fc receptor binding; antibody-dependent cell-mediated cytotoxicity (ADCC); phagocytosis; downregulation of cell surface receptors (e.g., B cell receptor); and B cell activation. It is known in the art that wild-type IgG4 antibodies have lower effector functions than wild-type IgG1 antibodies.

[0108]

[0118] The term "Fc region" as used herein refers to the C-terminal region of an immunoglobulin heavy chain comprising at least a portion of the constant region. This term includes native sequence Fc regions and variant Fc regions. In one embodiment, a human IgG heavy chain Fc region extends from Cys226, or from Pro230, to the carboxyl terminus of the heavy chain. However, the C-terminal lysine (Lys447) of the Fc region may or may not be present. Unless otherwise specified herein, the numbering of amino acid residues within an Fc region or constant region is according to the EU numbering system, also referred to as the EU index, as described in Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD, 1991.

[0109]

[0119] The terms "full length antibody," "intact antibody," and "whole antibody" are used interchangeably herein to refer to an antibody having a heavy chain having a structure substantially similar to a native antibody structure or including an Fc region as defined herein.

[0110]

[0120] A "natural antibody" or "natural antibodies" as used herein refers to naturally occurring immunoglobulin molecules with various structures. For example, a natural IgG antibody is a heterotetrameric glycoprotein of about 150,000 daltons composed of two identical light chains and two identical heavy chains that are disulfide-bonded. From the N-terminus to the C-terminus, each heavy chain has a variable region (VH), also called a variable heavy domain or a heavy chain variable domain, followed by three constant domains (CHI, CH2, and CH3). Similarly, from the N-terminus to the C-terminus, each light chain has a variable region (VL), also called a variable light domain or a light chain variable domain, followed by a constant light (CL) domain. The light chain of an antibody can be assigned to one of two types, called kappa (κ) and lambda (λ), based on the amino acid sequence of its constant domain.

[0111]

[0121] The present disclosure provides compositions suitable for subcutaneous administration, including high-capacity and high-dose brain-targeting antibodies or antigen-binding fragments thereof, which are useful, for example, in the treatment of Alzheimer's disease.

[0112] How to use

[0122] In one aspect, the disclosure provides a method for treating Alzheimer's disease in a subject, the method comprising subcutaneously administering to the subject a composition comprising a brain-targeting antibody or antigen-binding fragment thereof, wherein the brain-targeting antibody or antigen-binding fragment thereof is at a concentration of about 130 mg / mL to about 200 mg / mL.

[0113]

[0123] In one aspect, the disclosure provides a method for treating a subject at risk for Alzheimer's disease, the method comprising subcutaneously administering to the subject a composition comprising a brain-targeting antibody or antigen-binding fragment thereof, wherein the brain-targeting antibody or antigen-binding fragment thereof is at a concentration of about 130 mg / mL to about 200 mg / mL.

[0114]

[0124] In one aspect, the present disclosure provides a method for treating cognitive impairment in a subject, the method comprising subcutaneously administering to the subject a composition comprising a brain-targeting antibody or antigen-binding fragment thereof, wherein the brain-targeting antibody or antigen-binding fragment thereof is at a concentration of about 130 mg / mL to about 200 mg / mL. In some embodiments, the cognitive impairment is mild cognitive impairment (MCI). In some embodiments, the subject is suffering from Alzheimer's disease.

[0115]

[0125] In one aspect, the present disclosure provides a method for reducing cognitive impairment in a subject, the method comprising subcutaneously administering to the subject a composition comprising a brain-targeting antibody or antigen-binding fragment thereof, wherein the brain-targeting antibody or antigen-binding fragment thereof is at a concentration of about 130 mg / mL to about 200 mg / mL. In some embodiments, the cognitive impairment is mild cognitive impairment (MCI). In some embodiments, the subject is suffering from Alzheimer's disease.

[0116]

[0126] In one aspect, the present disclosure provides a method of slowing the progression of cognitive impairment in a subject, the method comprising subcutaneously administering to the subject a composition comprising a brain-targeting antibody or antigen-binding fragment thereof, wherein the brain-targeting antibody or antigen-binding fragment thereof is at a concentration of about 130 mg / mL to about 200 mg / mL. In some embodiments, the cognitive impairment is mild cognitive impairment (MCI). In some embodiments, the subject is afflicted with Alzheimer's disease.

[0117]

[0127] In one aspect, the disclosure provides a method of delaying progression of Alzheimer's disease (AD) in a subject diagnosed with early or mild-to-moderate AD, the method comprising subcutaneously administering to the subject a composition comprising a brain-targeting antibody or antigen-binding fragment thereof, wherein the brain-targeting antibody or antigen-binding fragment thereof is at a concentration of about 130 mg / mL to about 200 mg / mL.

[0118]

[0128] In one aspect, the disclosure provides a method of treating early or mild-to-moderate AD without increasing the risk of adverse events, the method comprising subcutaneously administering to a subject a composition comprising a brain-targeting antibody or antigen-binding fragment thereof, wherein the brain-targeting antibody or antigen-binding fragment thereof is at a concentration of about 130 mg / mL to about 200 mg / mL.

[0119]

[0129] In one aspect, the disclosure provides a method of delaying clinical deterioration in a patient in a subject diagnosed with early or mild-to-moderate Alzheimer's Disease (AD), the method comprising subcutaneously administering to the subject a composition comprising a brain-targeting antibody or antigen-binding fragment thereof, wherein the brain-targeting antibody or antigen-binding fragment thereof is at a concentration of about 130 mg / mL to about 200 mg / mL.

[0120]

[0130] In some embodiments, the brain-targeting antibody or antigen-binding fragment thereof is administered at a dose between about 400 mg and about 7500 mg. In some embodiments, the brain-targeting antibody or antigen-binding fragment thereof is administered at a dose between about 600 mg and about 7200 mg. In some embodiments, the brain-targeting antibody or antigen-binding fragment thereof is administered at a dose between about 1700 mg, about 3400 mg, or about 6800 mg. In some embodiments, the brain-targeting antibody is administered at a dose between about 400 mg and about 7500 mg. In some embodiments, the brain-targeting antibody is administered at a dose between about 600 mg and about 7200 mg. In some embodiments, the brain-targeting antibody is administered at a dose between about 1700 mg, about 3400 mg, or about 6800 mg.

[0121]

[0131] In some embodiments, the brain-targeting antibody or antigen-binding fragment thereof is administered in an injection volume of about 4 mg / mL to about 60 mL, hi some embodiments, the injection volume is about 10 mL to about 40 mL.

[0122]

[0132] In some embodiments, the brain-targeting antibody or antigen-binding fragment thereof is administered at a flow rate of about 1 mL / min to about 5 mL / min. In some embodiments, the flow rate is about 2 mL / min to about 4 mL / min.

[0123]

[0133] In some embodiments, the method further comprises administering to the subject a permeation enhancer. In some embodiments, the composition further comprises a hyaluronidase (e.g., Amphadase®, Hydase®, Hylenex®, and Vitrase®). In some embodiments, the permeation enhancer is recombinant human hyaluronidase. In some embodiments, the recombinant human hyaluronidase is a human soluble PH20 hyaluronidase glycoprotein, such as rHuPH20. In some embodiments, the permeation enhancer (e.g., hyaluronidase) is administered at a dose of about 500 U / ml to about 2000 U / mL. In some embodiments, the permeation enhancer (e.g., hyaluronidase) is administered at a dose of about 500 U / ml. In some embodiments, the permeation enhancer (e.g., hyaluronidase) is administered at a dose of about 1000 U / ml. In some embodiments, the permeation enhancer (e.g., hyaluronidase) is administered at a dose of about 1500 U / ml. In some embodiments, the permeation enhancer (e.g., hyaluronidase) is administered at a dose of about 2000 U / ml.

[0124]

[0134] In some embodiments, the brain-targeting antibody or antigen-binding fragment thereof and the permeation enhancer are administered simultaneously. In some embodiments, the brain-targeting antibody or antigen-binding fragment thereof and the permeation enhancer are administered sequentially. In some embodiments, the brain-targeting antibody or antigen-binding fragment thereof and the permeation enhancer are in the same composition. In some embodiments, the brain-targeting antibody or antigen-binding fragment thereof and the permeation enhancer are in separate compositions. In some embodiments, the anti-amyloid beta antibody or antigen-binding fragment thereof and the hyaluronidase are administered simultaneously. In some embodiments, the anti-amyloid beta antibody or antigen-binding fragment thereof and the hyaluronidase are administered sequentially. In some embodiments, the anti-amyloid beta antibody or antigen-binding fragment thereof and the hyaluronidase are in the same composition. In some embodiments, the anti-amyloid beta antibody or antigen-binding fragment thereof and the hyaluronidase are in separate compositions.

[0125]

[0135] In some embodiments, the Alzheimer's disease is autosomal dominant Alzheimer's disease. In some embodiments, the autosomal dominant Alzheimer's disease is prodromal, mild, moderate, or mild to moderate. In some embodiments, the autosomal dominant Alzheimer's disease is mild to moderate. In some embodiments, the Alzheimer's disease is sporadic AD. In some embodiments, the Alzheimer's disease is early or mild AD.

[0126]

[0136] In some embodiments, the subject is a human.

[0127]

[0137] In some embodiments, the method comprises subcutaneously administering to a subject a first dose of a brain-targeting antibody (e.g., crenezumab) or antigen-binding fragment thereof and a second dose of a brain-targeting antibody (e.g., crenezumab) or antigen-binding fragment thereof. In some embodiments, the second dose comprises twice the amount of the brain-targeting antibody (e.g., crenezumab) or antigen-binding fragment thereof as the first dose. In some embodiments, the first and second doses of the brain-targeting antibody (e.g., crenezumab) or antigen-binding fragment thereof are administered two weeks apart. In some embodiments, the first dose of the brain-targeting antibody (e.g., crenezumab) or antigen-binding fragment thereof is administered on day 1 and the second dose of the brain-targeting antibody (e.g., crenezumab) or antigen-binding fragment thereof is administered on day 15. In some embodiments, a first dose of a brain-targeting antibody (e.g., crenezumab) or antigen-binding fragment thereof is administered with a first dose of a penetration enhancer (e.g., hyaluronidase), and a second dose of a brain-targeting antibody (e.g., crenezumab) or antigen-binding fragment thereof is administered with a second dose of a penetration enhancer (e.g., hyaluronidase). In some embodiments, the second dose of a penetration enhancer (e.g., hyaluronidase) comprises half the amount of the first dose of a penetration enhancer (e.g., hyaluronidase). In some embodiments, the second dose of a penetration enhancer (e.g., hyaluronidase) comprises a quarter of the amount of the first dose of a penetration enhancer (e.g., hyaluronidase).

[0128]

[0138] In some embodiments, the disclosure provides a method for treating cognitive impairment in a subject, the method comprising subcutaneously administering to the subject a first dose and a second dose, where (a) the first dose comprises about 1700 mg of a brain-targeting antibody or antigen-binding fragment thereof and is administered in an injection volume of 10 mL at a flow rate of about 2 mL / min; (b) the second dose comprises about 3400 mg of a brain-targeting antibody or antigen-binding fragment thereof and is administered in an injection volume of 20 mL at a flow rate of about 2 mL / min. In some embodiments, the first dose is administered on day 1 and the second dose is administered on day 15.

[0129]

[0139] In some embodiments, the disclosure provides a method for treating a cognitive impairment in a subject, the method comprising subcutaneously administering to the subject a first dose and a second dose; (a) a first dose comprises about 3400 mg of a brain-targeting antibody or antigen-binding fragment thereof and is administered in an injection volume of 20 mL at a flow rate of about 4 mL / min; said first dose is co-administered with a permeation enhancer at a dose of about 2000 U / mL; (b) a second dose comprising about 6800 mg of the brain-targeting antibody or antigen-binding fragment thereof administered in a 40 mL injection volume at a flow rate of about 4 mL / min; said second dose is co-administered with a permeation enhancer at a dose of about 1000 U / mL. In some embodiments, the first dose and the permeation enhancer (at a dose of about 2000 U / mL) are administered on day 1, and the second dose and the permeation enhancer (at a dose of about 1000 U / mL) are administered on day 15.

[0130]

[0140] In some embodiments, the disclosure provides a method for treating a cognitive impairment in a subject, the method comprising subcutaneously administering to the subject a first dose and a second dose; (a) a first dose comprises about 3400 mg of a brain-targeting antibody or antigen-binding fragment thereof and is administered in an injection volume of 20 mL at a flow rate of about 4 mL / min; said first dose is co-administered with hyaluronidase at a dose of about 2000 U / mL; (b) a second dose comprising about 6800 mg of a brain-targeting antibody or antigen-binding fragment thereof administered in an injection volume of 40 mL at a flow rate of about 4 mL / min; said second dose is co-administered with hyaluronidase at a dose of about 1000 U / mL. In some embodiments, the first dose and hyaluronidase (at a dose of about 2000 U / mL) are administered on day 1 and the second dose and hyaluronidase (at a dose of about 1000 U / mL) are administered on day 15.

[0131]

[0141] In some embodiments, the disclosure provides a method for treating a cognitive impairment in a subject, the method comprising subcutaneously administering to the subject a first dose and a second dose; (a) a first dose comprises about 3400 mg of a brain-targeting antibody or antigen-binding fragment thereof, administered in an injection volume of 20 mL at a flow rate of about 4 mL / min; said first dose is co-administered with recombinant human hyaluronidase at a dose of about 2000 U / mL; (b) a second dose comprising about 6800 mg of a brain-targeting antibody or antigen-binding fragment thereof administered in an injection volume of 40 mL at a flow rate of about 4 mL / min; said second dose is co-administered with recombinant human hyaluronidase at a dose of about 1000 U / mL. In some embodiments, the first dose and recombinant human hyaluronidase (at a dose of about 2000 U / mL) are administered on day 1 and the second dose and recombinant human hyaluronidase (at a dose of about 1000 U / mL) are administered on day 15.

[0132]

[0142] In some embodiments, the disclosure provides a method for treating a cognitive impairment in a subject, the method comprising subcutaneously administering to the subject a first dose and a second dose, where (a) the first dose comprises about 1700 mg of a brain-targeting antibody or antigen-binding fragment thereof and is administered in an injection volume of 10 mL at a flow rate of about 4 mL / min; (b) the second dose comprises about 3400 mg of a brain-targeting antibody or antigen-binding fragment thereof and is administered in an injection volume of 40 mL at a flow rate of about 4 mL / min. In some embodiments, the first dose is administered on day 1 and the second dose is administered on day 15.

[0133]

[0143] In some embodiments, the disclosure provides a method for treating a cognitive impairment in a subject, the method comprising subcutaneously administering to the subject a first dose and a second dose; (a) the first dose comprises about 3400 mg of a brain-targeting antibody or antigen-binding fragment thereof and is administered in an injection volume of 20 mL at a flow rate of about 4 mL / min; (b) a second dose comprising about 6800 mg of the brain-targeting antibody or antigen-binding fragment thereof administered in an injection volume of 40 mL at a flow rate of about 4 mL / min; said second dose is co-administered with a permeation enhancer at a dose of about 500 U / mL. In some embodiments, the first dose is administered on day 1 and the second dose and the permeation enhancer are administered on day 15.

[0134]

[0144] In some embodiments, the disclosure provides a method for treating a cognitive impairment in a subject, the method comprising subcutaneously administering to the subject a first dose and a second dose; (a) the first dose comprises about 3400 mg of a brain-targeting antibody or antigen-binding fragment thereof and is administered in an injection volume of 20 mL at a flow rate of about 4 mL / min; (b) a second dose comprising about 6800 mg of a brain-targeting antibody or antigen-binding fragment thereof administered in an injection volume of 40 mL at a flow rate of about 4 mL / min; said second dose is co-administered with hyaluronidase at a dose of about 500 U / mL. In some embodiments, the first dose is administered on day 1 and the second dose and hyaluronidase are administered on day 15.

[0135]

[0145] In some embodiments, the disclosure provides a method for treating a cognitive impairment in a subject, the method comprising subcutaneously administering to the subject a first dose and a second dose; (a) the first dose comprises about 3400 mg of a brain-targeting antibody or antigen-binding fragment thereof and is administered in an injection volume of 20 mL at a flow rate of about 4 mL / min; (b) a second dose comprising about 6800 mg of a brain-targeting antibody or antigen-binding fragment thereof administered in an injection volume of 40 mL at a flow rate of about 4 mL / min; said second dose is co-administered with recombinant human hyaluronidase at a dose of about 500 U / mL. In some embodiments, the first dose is administered on day 1 and the second dose and recombinant human hyaluronidase are administered on day 15.

[0136]

[0146] In some embodiments, the disclosure provides a method for treating a cognitive impairment in a subject, the method comprising subcutaneously administering to the subject a first dose and a second dose; (a) a first dose comprises about 3400 mg of a brain-targeting antibody or antigen-binding fragment thereof and is administered in an injection volume of 20 mL at a flow rate of about 4 mL / min; said first dose is co-administered with a permeation enhancer at a dose of about 2000 U / mL; (b) a second dose comprising about 6800 mg of a brain-targeting antibody or antigen-binding fragment thereof administered in a 40 mL injection volume at a flow rate of about 4 mL / min; said second dose is co-administered with a permeation enhancer at a dose of about 500 U / mL. In some embodiments, the first dose and recombinant human hyaluronidase (at a dose of about 2000 U / mL) are administered on day 1 and the second dose and the permeation enhancer (at a dose of about 500 U / mL) are administered on day 15.

[0137]

[0147] In some embodiments, the disclosure provides a method for treating a cognitive impairment in a subject, the method comprising subcutaneously administering to the subject a first dose and a second dose; (a) a first dose comprises about 3400 mg of a brain-targeting antibody or antigen-binding fragment thereof and is administered in an injection volume of 20 mL at a flow rate of about 4 mL / min; said first dose is co-administered with hyaluronidase at a dose of about 2000 U / mL; (b) a second dose comprising about 6800 mg of a brain-targeting antibody or antigen-binding fragment thereof administered in an injection volume of 40 mL at a flow rate of about 4 mL / min; said second dose is co-administered with hyaluronidase at a dose of about 500 U / mL. In some embodiments, the first dose and hyaluronidase (at a dose of about 2000 U / mL) are administered on day 1 and the second dose and recombinant human hyaluronidase (at a dose of about 500 U / mL) are administered on day 15.

[0138]

[0148] In some embodiments, the disclosure provides a method for treating a cognitive impairment in a subject, the method comprising subcutaneously administering to the subject a first dose and a second dose; (a) a first dose comprises about 3400 mg of a brain-targeting antibody or antigen-binding fragment thereof, administered in an injection volume of 20 mL at a flow rate of about 4 mL / min; said first dose is co-administered with recombinant human hyaluronidase at a dose of about 2000 U / mL; (b) a second dose comprising about 6800 mg of a brain-targeting antibody or antigen-binding fragment thereof administered in an injection volume of 40 mL at a flow rate of about 4 mL / min; said second dose is co-administered with recombinant human hyaluronidase at a dose of about 500 U / mL. In some embodiments, the first dose and recombinant human hyaluronidase (at a dose of about 2000 U / mL) are administered on day 1 and the second dose and recombinant human hyaluronidase (at a dose of about 500 U / mL) are administered on day 15.

[0139]

[0149] In some embodiments, the disclosure provides a method for treating a cognitive impairment in a subject, the method comprising subcutaneously administering to the subject a composition comprising about 6800 mg of a brain-targeting antibody or antigen-binding fragment thereof administered at a flow rate of about 4 mL / min in an injection volume of about 40 mL and a permeation enhancer at a dose of about 500 U / mL.

[0140]

[0150] In some embodiments, the disclosure provides a method for treating a cognitive impairment in a subject, the method comprising subcutaneously administering to the subject a composition comprising about 6800 mg of a brain-targeting antibody or antigen-binding fragment thereof administered at a flow rate of about 4 mL / min in an injection volume of about 40 mL and hyaluronidase at a dose of about 500 U / mL.

[0141]

[0151] In some embodiments, the disclosure provides a method for treating a cognitive impairment in a subject, the method comprising subcutaneously administering to the subject a composition comprising about 6800 mg of a brain-targeting antibody or antigen-binding fragment thereof administered at a flow rate of about 4 mL / min in an injection volume of about 40 mL and recombinant human hyaluronidase at a dose of about 500 U / mL.

[0142]

[0152] In some embodiments, the disclosure provides a method for treating Alzheimer's disease in a subject, the method comprising subcutaneously administering to the subject a first dose and a second dose, where (a) the first dose comprises about 1700 mg of a brain-targeting antibody or antigen-binding fragment thereof and is administered in an injection volume of 10 mL at a flow rate of about 2 mL / min; and (b) the second dose comprises about 3400 mg of a brain-targeting antibody or antigen-binding fragment thereof and is administered in an injection volume of 20 mL at a flow rate of about 2 mL / min. In some embodiments, the first dose is administered on day 1 and the second dose is administered on day 15.

[0143]

[0153] In some embodiments, the disclosure provides a method for treating Alzheimer's disease in a subject, the method comprising subcutaneously administering to the subject a first dose and a second dose; (a) a first dose comprises about 3400 mg of a brain-targeting antibody or antigen-binding fragment thereof and is administered in an injection volume of 20 mL at a flow rate of about 4 mL / min; said first dose is co-administered with a permeation enhancer at a dose of about 2000 U / mL; (b) a second dose comprising about 6800 mg of the brain-targeting antibody or antigen-binding fragment thereof administered in a 40 mL injection volume at a flow rate of about 4 mL / min; said second dose is co-administered with a permeation enhancer at a dose of about 1000 U / mL. In some embodiments, the first dose and the permeation enhancer (at a dose of about 2000 U / mL) are administered on day 1, and the second dose and the permeation enhancer (at a dose of about 1000 U / mL) are administered on day 15.

[0144]

[0154] In some embodiments, the disclosure provides a method for treating Alzheimer's disease in a subject, the method comprising subcutaneously administering to the subject a first dose and a second dose; (a) a first dose comprises about 3400 mg of a brain-targeting antibody or antigen-binding fragment thereof and is administered in an injection volume of 20 mL at a flow rate of about 4 mL / min; said first dose is co-administered with hyaluronidase at a dose of about 2000 U / mL; (b) a second dose comprising about 6800 mg of a brain-targeting antibody or antigen-binding fragment thereof administered in an injection volume of 40 mL at a flow rate of about 4 mL / min; said second dose is co-administered with hyaluronidase at a dose of about 1000 U / mL. In some embodiments, the first dose and hyaluronidase (at a dose of about 2000 U / mL) are administered on day 1 and the second dose and hyaluronidase (at a dose of about 1000 U / mL) are administered on day 15.

[0145]

[0155] In some embodiments, the disclosure provides a method for treating Alzheimer's disease in a subject, the method comprising subcutaneously administering to the subject a first dose and a second dose; (a) a first dose comprises about 3400 mg of a brain-targeting antibody or antigen-binding fragment thereof, administered in an injection volume of 20 mL at a flow rate of about 4 mL / min; said first dose is co-administered with recombinant human hyaluronidase at a dose of about 2000 U / mL; (b) a second dose comprising about 6800 mg of a brain-targeting antibody or antigen-binding fragment thereof administered in an injection volume of 40 mL at a flow rate of about 4 mL / min; said second dose is co-administered with recombinant human hyaluronidase at a dose of about 1000 U / mL. In some embodiments, the first dose and recombinant human hyaluronidase (at a dose of about 2000 U / mL) are administered on day 1 and the second dose and recombinant human hyaluronidase (at a dose of about 1000 U / mL) are administered on day 15.

[0146]

[0156] In some embodiments, the disclosure provides a method for treating Alzheimer's disease in a subject, the method comprising subcutaneously administering to the subject a first dose and a second dose, where (a) the first dose comprises about 1700 mg of a brain-targeting antibody or antigen-binding fragment thereof and is administered in an injection volume of 10 mL at a flow rate of about 4 mL / min; and (b) the second dose comprises about 3400 mg of a brain-targeting antibody or antigen-binding fragment thereof and is administered in an injection volume of 40 mL at a flow rate of about 4 mL / min. In some embodiments, the first dose is administered on day 1 and the second dose is administered on day 15.

[0147]

[0157] In some embodiments, the disclosure provides a method for treating Alzheimer's disease in a subject, the method comprising subcutaneously administering to the subject a first dose and a second dose; (a) the first dose comprises about 3400 mg of a brain-targeting antibody or antigen-binding fragment thereof and is administered in an injection volume of 20 mL at a flow rate of about 4 mL / min; (b) a second dose comprising about 6800 mg of the brain-targeting antibody or antigen-binding fragment thereof administered in an injection volume of 40 mL at a flow rate of about 4 mL / min; said second dose is co-administered with a permeation enhancer at a dose of about 500 U / mL. In some embodiments, the first dose is administered on day 1 and the second dose and the permeation enhancer are administered on day 15.

[0148]

[0158] In some embodiments, the disclosure provides a method for treating Alzheimer's disease in a subject, the method comprising subcutaneously administering to the subject a first dose and a second dose; (a) the first dose comprises about 3400 mg of a brain-targeting antibody or antigen-binding fragment thereof and is administered in an injection volume of 20 mL at a flow rate of about 4 mL / min; (b) a second dose comprising about 6800 mg of a brain-targeting antibody or antigen-binding fragment thereof administered in an injection volume of 40 mL at a flow rate of about 4 mL / min; said second dose is co-administered with hyaluronidase at a dose of about 500 U / mL. In some embodiments, the first dose is administered on day 1 and the second dose and hyaluronidase are administered on day 15.

[0149]

[0159] In some embodiments, the disclosure provides a method for treating Alzheimer's disease in a subject, the method comprising subcutaneously administering to the subject a first dose and a second dose; (a) the first dose comprises about 3400 mg of a brain-targeting antibody or antigen-binding fragment thereof and is administered in an injection volume of 20 mL at a flow rate of about 4 mL / min; (b) a second dose comprising about 6800 mg of a brain-targeting antibody or antigen-binding fragment thereof administered in an injection volume of 40 mL at a flow rate of about 4 mL / min; said second dose is co-administered with recombinant human hyaluronidase at a dose of about 500 U / mL. In some embodiments, the first dose is administered on day 1 and the second dose and recombinant human hyaluronidase are administered on day 15.

[0150]

[0160] In some embodiments, the disclosure provides a method for treating Alzheimer's disease in a subject, the method comprising subcutaneously administering to the subject a first dose and a second dose; (a) a first dose comprises about 3400 mg of a brain-targeting antibody or antigen-binding fragment thereof and is administered in an injection volume of 20 mL at a flow rate of about 4 mL / min; said first dose is co-administered with a permeation enhancer at a dose of about 2000 U / mL; (b) a second dose comprising about 6800 mg of the brain-targeting antibody or antigen-binding fragment thereof administered in a 40 mL injection volume at a flow rate of about 4 mL / min; said second dose is co-administered with a permeation enhancer at a dose of about 500 U / mL. In some embodiments, the first dose and the permeation enhancer (at a dose of about 2000 U / mL) are administered on day 1, and the second dose and the permeation enhancer (at a dose of about 500 U / mL) are administered on day 15.

[0151]

[0161] In some embodiments, the disclosure provides a method for treating Alzheimer's disease in a subject, the method comprising subcutaneously administering to the subject a first dose and a second dose; (a) a first dose comprises about 3400 mg of a brain-targeting antibody or antigen-binding fragment thereof and is administered in an injection volume of 20 mL at a flow rate of about 4 mL / min; said first dose is co-administered with hyaluronidase at a dose of about 2000 U / mL; (b) a second dose comprising about 6800 mg of a brain-targeting antibody or antigen-binding fragment thereof administered in an injection volume of 40 mL at a flow rate of about 4 mL / min; said second dose is co-administered with hyaluronidase at a dose of about 500 U / mL. In some embodiments, the first dose and hyaluronidase (at a dose of about 2000 U / mL) are administered on day 1 and the second dose and hyaluronidase (at a dose of about 500 U / mL) are administered on day 15.

[0152]

[0162] In some embodiments, the disclosure provides a method for treating Alzheimer's disease in a subject, the method comprising subcutaneously administering to the subject a first dose and a second dose; (a) a first dose comprises about 3400 mg of a brain-targeting antibody or antigen-binding fragment thereof, administered in an injection volume of 20 mL at a flow rate of about 4 mL / min; said first dose is co-administered with recombinant human hyaluronidase at a dose of about 2000 U / mL; (b) a second dose comprising about 6800 mg of a brain-targeting antibody or antigen-binding fragment thereof administered in an injection volume of 40 mL at a flow rate of about 4 mL / min; said second dose is co-administered with recombinant human hyaluronidase at a dose of about 500 U / mL. In some embodiments, the first dose and recombinant human hyaluronidase (at a dose of about 2000 U / mL) are administered on day 1 and the second dose and recombinant human hyaluronidase (at a dose of about 500 U / mL) are administered on day 15.

[0153]

[0163] In some embodiments, the disclosure provides a method for treating Alzheimer's disease in a subject, the method comprising subcutaneously administering to the subject a composition comprising about 6800 mg of a brain-targeting antibody or antigen-binding fragment thereof administered at a flow rate of about 4 mL / min in an injection volume of about 40 mL and a permeation enhancer at a dose of about 500 U / mL.

[0154]

[0164] In some embodiments, the disclosure provides a method for treating Alzheimer's disease in a subject, the method comprising subcutaneously administering to the subject a composition comprising about 6800 mg of a brain-targeting antibody or antigen-binding fragment thereof administered at a flow rate of about 4 mL / min in an injection volume of about 40 mL and hyaluronidase at a dose of about 500 U / mL.

[0155]

[0165] In some embodiments, the disclosure provides a method for treating Alzheimer's disease in a subject, the method comprising subcutaneously administering to the subject a composition comprising about 6800 mg of a brain-targeting antibody or antigen-binding fragment thereof administered at a flow rate of about 4 mL / min in an injection volume of about 40 mL and recombinant human hyaluronidase at a dose of about 500 U / mL.

[0156]

[0166] In some embodiments, the disclosure provides a method for treating a subject at risk for Alzheimer's disease, the method comprising subcutaneously administering to the subject a first dose and a second dose, where (a) the first dose comprises about 1700 mg of a brain-targeting antibody or antigen-binding fragment thereof and is administered in an injection volume of 10 mL at a flow rate of about 2 mL / min; and (b) the second dose comprises about 3400 mg of a brain-targeting antibody or antigen-binding fragment thereof and is administered in an injection volume of 20 mL at a flow rate of about 2 mL / min. In some embodiments, the first dose is administered on day 1 and the second dose is administered on day 15.

[0157]

[0167] In some embodiments, the disclosure provides a method for treating a subject at risk for Alzheimer's disease, the method comprising subcutaneously administering to the subject a first dose and a second dose; (a) a first dose comprises about 3400 mg of a brain-targeting antibody or antigen-binding fragment thereof and is administered in an injection volume of 20 mL at a flow rate of about 4 mL / min; said first dose is co-administered with a permeation enhancer at a dose of about 2000 U / mL; (b) a second dose comprising about 6800 mg of the brain-targeting antibody or antigen-binding fragment thereof administered in a 40 mL injection volume at a flow rate of about 4 mL / min; said second dose is co-administered with a permeation enhancer at a dose of about 1000 U / mL. In some embodiments, the first dose and the permeation enhancer (at a dose of about 2000 U / mL) are administered on day 1, and the second dose and the permeation enhancer (at a dose of about 1000 U / mL) are administered on day 15.

[0158]

[0168] In some embodiments, the disclosure provides a method for treating a subject at risk for Alzheimer's disease, the method comprising subcutaneously administering to the subject a first dose and a second dose; (a) a first dose comprises about 3400 mg of a brain-targeting antibody or antigen-binding fragment thereof and is administered in an injection volume of 20 mL at a flow rate of about 4 mL / min; said first dose is co-administered with hyaluronidase at a dose of about 2000 U / mL; (b) a second dose comprising about 6800 mg of a brain-targeting antibody or antigen-binding fragment thereof administered in an injection volume of 40 mL at a flow rate of about 4 mL / min; said second dose is co-administered with hyaluronidase at a dose of about 1000 U / mL. In some embodiments, the first dose and hyaluronidase (at a dose of about 2000 U / mL) are administered on day 1 and the second dose and hyaluronidase (at a dose of about 1000 U / mL) are administered on day 15.

[0159]

[0169] In some embodiments, the disclosure provides a method for treating a subject at risk for Alzheimer's disease, the method comprising subcutaneously administering to the subject a first dose and a second dose; (a) a first dose comprises about 3400 mg of a brain-targeting antibody or antigen-binding fragment thereof, administered in an injection volume of 20 mL at a flow rate of about 4 mL / min; said first dose is co-administered with recombinant human hyaluronidase at a dose of about 2000 U / mL; (b) a second dose comprising about 6800 mg of a brain-targeting antibody or antigen-binding fragment thereof administered in an injection volume of 40 mL at a flow rate of about 4 mL / min; said second dose is co-administered with recombinant human hyaluronidase at a dose of about 1000 U / mL. In some embodiments, the first dose and recombinant human hyaluronidase (at a dose of about 2000 U / mL) are administered on day 1 and the second dose and recombinant human hyaluronidase (at a dose of about 1000 U / mL) are administered on day 15.

[0160]

[0170] In some embodiments, the disclosure provides a method for treating a subject at risk for Alzheimer's disease, the method comprising subcutaneously administering to the subject a first dose and a second dose, where (a) the first dose comprises about 1700 mg of a brain-targeting antibody or antigen-binding fragment thereof and is administered in an injection volume of 10 mL at a flow rate of about 4 mL / min; and (b) the second dose comprises about 3400 mg of a brain-targeting antibody or antigen-binding fragment thereof and is administered in an injection volume of 40 mL at a flow rate of about 4 mL / min. In some embodiments, the first dose is administered on day 1 and the second dose is administered on day 15.

[0161]

[0171] In some embodiments, the disclosure provides a method for treating a subject at risk for Alzheimer's disease, the method comprising subcutaneously administering to the subject a first dose and a second dose; (a) the first dose comprises about 3400 mg of a brain-targeting antibody or antigen-binding fragment thereof and is administered in an injection volume of 20 mL at a flow rate of about 4 mL / min; (b) a second dose comprising about 6800 mg of the brain-targeting antibody or antigen-binding fragment thereof administered in an injection volume of 40 mL at a flow rate of about 4 mL / min; said second dose is co-administered with a permeation enhancer at a dose of about 500 U / mL. In some embodiments, the first dose is administered on day 1 and the second dose and the permeation enhancer are administered on day 15.

[0162]

[0172] In some embodiments, the disclosure provides a method for treating a subject at risk for Alzheimer's disease, the method comprising subcutaneously administering to the subject a first dose and a second dose; (a) the first dose comprises about 3400 mg of a brain-targeting antibody or antigen-binding fragment thereof and is administered in an injection volume of 20 mL at a flow rate of about 4 mL / min; (b) a second dose comprising about 6800 mg of a brain-targeting antibody or antigen-binding fragment thereof administered in an injection volume of 40 mL at a flow rate of about 4 mL / min; said second dose is co-administered with hyaluronidase at a dose of about 500 U / mL. In some embodiments, the first dose is administered on day 1 and the second dose and hyaluronidase are administered on day 15.

[0163]

[0173] In some embodiments, the disclosure provides a method for treating a subject at risk for Alzheimer's disease, the method comprising subcutaneously administering to the subject a first dose and a second dose; (a) the first dose comprises about 3400 mg of a brain-targeting antibody or antigen-binding fragment thereof and is administered in an injection volume of 20 mL at a flow rate of about 4 mL / min; (b) a second dose comprising about 6800 mg of a brain-targeting antibody or antigen-binding fragment thereof administered in an injection volume of 40 mL at a flow rate of about 4 mL / min; said second dose is co-administered with recombinant human hyaluronidase at a dose of about 500 U / mL. In some embodiments, the first dose is administered on day 1 and the second dose and recombinant human hyaluronidase are administered on day 15.

[0164]

[0174] In some embodiments, the disclosure provides a method for treating a subject at risk for Alzheimer's disease, the method comprising subcutaneously administering to the subject a first dose and a second dose; (a) a first dose comprises about 3400 mg of a brain-targeting antibody or antigen-binding fragment thereof and is administered in an injection volume of 20 mL at a flow rate of about 4 mL / min; said first dose is co-administered with a permeation enhancer at a dose of about 2000 U / mL; (b) a second dose comprising about 6800 mg of the brain-targeting antibody or antigen-binding fragment thereof administered in a 40 mL injection volume at a flow rate of about 4 mL / min; said second dose is co-administered with a permeation enhancer at a dose of about 500 U / mL. In some embodiments, the first dose and the permeation enhancer (at a dose of about 2000 U / mL) are administered on day 1, and the second dose and the permeation enhancer (at a dose of about 500 U / mL) are administered on day 15.

[0165]

[0175] In some embodiments, the disclosure provides a method for treating a subject at risk for Alzheimer's disease, the method comprising subcutaneously administering to the subject a first dose and a second dose; (a) a first dose comprises about 3400 mg of a brain-targeting antibody or antigen-binding fragment thereof and is administered in an injection volume of 20 mL at a flow rate of about 4 mL / min; said first dose is co-administered with hyaluronidase at a dose of about 2000 U / mL; (b) a second dose comprising about 6800 mg of a brain-targeting antibody or antigen-binding fragment thereof administered in an injection volume of 40 mL at a flow rate of about 4 mL / min; said second dose is co-administered with hyaluronidase at a dose of about 500 U / mL. In some embodiments, the first dose and hyaluronidase (at a dose of about 2000 U / mL) are administered on day 1 and the second dose and hyaluronidase (at a dose of about 500 U / mL) are administered on day 15.

[0166]

[0176] In some embodiments, the disclosure provides a method for treating a subject at risk for Alzheimer's disease, the method comprising subcutaneously administering to the subject a first dose and a second dose; (a) a first dose comprises about 3400 mg of a brain-targeting antibody or antigen-binding fragment thereof, administered in an injection volume of 20 mL at a flow rate of about 4 mL / min; said first dose is co-administered with recombinant human hyaluronidase at a dose of about 2000 U / mL; (b) a second dose comprising about 6800 mg of a brain-targeting antibody or antigen-binding fragment thereof administered in an injection volume of 40 mL at a flow rate of about 4 mL / min; said second dose is co-administered with recombinant human hyaluronidase at a dose of about 500 U / mL. In some embodiments, the first dose and recombinant human hyaluronidase (at a dose of about 2000 U / mL) are administered on day 1 and the second dose and recombinant human hyaluronidase (at a dose of about 500 U / mL) are administered on day 15.

[0167]

[0177] In some embodiments, the disclosure provides a method for treating a subject at risk for Alzheimer's disease, the method comprising subcutaneously administering to the subject a composition comprising about 6800 mg of a brain-targeting antibody or antigen-binding fragment thereof administered at a flow rate of about 4 mL / min in an injection volume of about 40 mL, and a permeation enhancer at a dose of about 500 U / mL.

[0168]

[0178] In some embodiments, the disclosure provides a method for treating a subject at risk for Alzheimer's disease, the method comprising subcutaneously administering to the subject a composition comprising about 6800 mg of a brain-targeting antibody or antigen-binding fragment thereof administered at a flow rate of about 4 mL / min in an injection volume of about 40 mL and hyaluronidase at a dose of about 500 U / mL.

[0169]

[0179] In some embodiments, the disclosure provides a method for treating a subject at risk for Alzheimer's disease, the method comprising subcutaneously administering to the subject a composition comprising about 6800 mg of a brain-targeting antibody or antigen-binding fragment thereof administered at a flow rate of about 4 mL / min in an injection volume of about 40 mL and recombinant human hyaluronidase at a dose of about 500 U / mL.

[0170]

[0180] In some embodiments, the disclosure provides a method for reducing cognitive impairment in a subject, the method comprising subcutaneously administering to the subject a first dose and a second dose, where (a) the first dose comprises about 1700 mg of a brain-targeting antibody or antigen-binding fragment thereof and is administered in an injection volume of 10 mL at a flow rate of about 2 mL / min; (b) the second dose comprises about 3400 mg of a brain-targeting antibody or antigen-binding fragment thereof and is administered in an injection volume of 20 mL at a flow rate of about 2 mL / min. In some embodiments, the first dose is administered on day 1 and the second dose is administered on day 15.

[0171]

[0181] In some embodiments, the disclosure provides a method for reducing cognitive impairment in a subject, the method comprising subcutaneously administering to the subject a first dose and a second dose; (a) a first dose comprises about 3400 mg of a brain-targeting antibody or antigen-binding fragment thereof and is administered in an injection volume of 20 mL at a flow rate of about 4 mL / min; said first dose is co-administered with a permeation enhancer at a dose of about 2000 U / mL; (b) a second dose comprising about 6800 mg of the brain-targeting antibody or antigen-binding fragment thereof administered in a 40 mL injection volume at a flow rate of about 4 mL / min; said second dose is co-administered with a permeation enhancer at a dose of about 1000 U / mL. In some embodiments, the first dose and the permeation enhancer (at a dose of about 2000 U / mL) are administered on day 1, and the second dose and the permeation enhancer (at a dose of about 1000 U / mL) are administered on day 15.

[0172]

[0182] In some embodiments, the disclosure provides a method for reducing cognitive impairment in a subject, the method comprising subcutaneously administering to the subject a first dose and a second dose; (a) a first dose comprises about 3400 mg of a brain-targeting antibody or antigen-binding fragment thereof and is administered in an injection volume of 20 mL at a flow rate of about 4 mL / min; said first dose is co-administered with hyaluronidase at a dose of about 2000 U / mL; (b) a second dose comprising about 6800 mg of a brain-targeting antibody or antigen-binding fragment thereof administered in an injection volume of 40 mL at a flow rate of about 4 mL / min; said second dose is co-administered with hyaluronidase at a dose of about 1000 U / mL. In some embodiments, the first dose and hyaluronidase (at a dose of about 2000 U / mL) are administered on day 1 and the second dose and hyaluronidase (at a dose of about 1000 U / mL) are administered on day 15.

[0173]

[0183] In some embodiments, the disclosure provides a method for reducing cognitive impairment in a subject, the method comprising subcutaneously administering to the subject a first dose and a second dose; (a) a first dose comprises about 3400 mg of a brain-targeting antibody or antigen-binding fragment thereof, administered in an injection volume of 20 mL at a flow rate of about 4 mL / min; said first dose is co-administered with recombinant human hyaluronidase at a dose of about 2000 U / mL; (b) a second dose comprising about 6800 mg of a brain-targeting antibody or antigen-binding fragment thereof administered in an injection volume of 40 mL at a flow rate of about 4 mL / min; said second dose is co-administered with recombinant human hyaluronidase at a dose of about 1000 U / mL. In some embodiments, the first dose and recombinant human hyaluronidase (at a dose of about 2000 U / mL) are administered on day 1 and the second dose and recombinant human hyaluronidase (at a dose of about 1000 U / mL) are administered on day 15.

[0174]

[0184] In some embodiments, the disclosure provides a method for reducing cognitive impairment in a subject, the method comprising subcutaneously administering to the subject a first dose and a second dose, where (a) the first dose comprises about 1700 mg of a brain-targeting antibody or antigen-binding fragment thereof and is administered in an injection volume of 10 mL at a flow rate of about 4 mL / min; (b) the second dose comprises about 3400 mg of a brain-targeting antibody or antigen-binding fragment thereof and is administered in an injection volume of 40 mL at a flow rate of about 4 mL / min. In some embodiments, the first dose is administered on day 1 and the second dose is administered on day 15.

[0175]

[0185] In some embodiments, the disclosure provides a method for reducing cognitive impairment in a subject, the method comprising subcutaneously administering to the subject a first dose and a second dose; (a) the first dose comprises about 3400 mg of a brain-targeting antibody or antigen-binding fragment thereof and is administered in an injection volume of 20 mL at a flow rate of about 4 mL / min; (b) a second dose comprising about 6800 mg of the brain-targeting antibody or antigen-binding fragment thereof administered in an injection volume of 40 mL at a flow rate of about 4 mL / min; said second dose is co-administered with a permeation enhancer at a dose of about 500 U / mL. In some embodiments, the first dose is administered on day 1 and the second dose and the permeation enhancer are administered on day 15.

[0176]

[0186] In some embodiments, the disclosure provides a method for reducing cognitive impairment in a subject, the method comprising subcutaneously administering to the subject a first dose and a second dose; (a) the first dose comprises about 3400 mg of a brain-targeting antibody or antigen-binding fragment thereof and is administered in an injection volume of 20 mL at a flow rate of about 4 mL / min; (b) a second dose comprising about 6800 mg of a brain-targeting antibody or antigen-binding fragment thereof administered in an injection volume of 40 mL at a flow rate of about 4 mL / min; said second dose is co-administered with hyaluronidase at a dose of about 500 U / mL. In some embodiments, the first dose is administered on day 1 and the second dose and hyaluronidase are administered on day 15.

[0177]

[0187] In some embodiments, the disclosure provides a method for reducing cognitive impairment in a subject, the method comprising subcutaneously administering to the subject a first dose and a second dose; (a) the first dose comprises about 3400 mg of a brain-targeting antibody or antigen-binding fragment thereof and is administered in an injection volume of 20 mL at a flow rate of about 4 mL / min; (b) a second dose comprising about 6800 mg of a brain-targeting antibody or antigen-binding fragment thereof administered in an injection volume of 40 mL at a flow rate of about 4 mL / min; said second dose is co-administered with recombinant human hyaluronidase at a dose of about 500 U / mL. In some embodiments, the first dose is administered on day 1 and the second dose and recombinant human hyaluronidase are administered on day 15.

[0178]

[0188] In some embodiments, the disclosure provides a method for reducing cognitive impairment in a subject, the method comprising subcutaneously administering to the subject a first dose and a second dose; (a) a first dose comprises about 3400 mg of a brain-targeting antibody or antigen-binding fragment thereof and is administered in an injection volume of 20 mL at a flow rate of about 4 mL / min; said first dose is co-administered with a permeation enhancer at a dose of about 2000 U / mL; (b) a second dose comprising about 6800 mg of the brain-targeting antibody or antigen-binding fragment thereof administered in a 40 mL injection volume at a flow rate of about 4 mL / min; said second dose is co-administered with a permeation enhancer at a dose of about 500 U / mL. In some embodiments, the first dose and the permeation enhancer (at a dose of about 2000 U / mL) are administered on day 1, and the second dose and the permeation enhancer (at a dose of about 500 U / mL) are administered on day 15.

[0179]

[0189] In some embodiments, the disclosure provides a method for reducing cognitive impairment in a subject, the method comprising subcutaneously administering to the subject a first dose and a second dose; (a) a first dose comprises about 3400 mg of a brain-targeting antibody or antigen-binding fragment thereof and is administered in an injection volume of 20 mL at a flow rate of about 4 mL / min; said first dose is co-administered with hyaluronidase at a dose of about 2000 U / mL; (b) a second dose comprising about 6800 mg of a brain-targeting antibody or antigen-binding fragment thereof administered in an injection volume of 40 mL at a flow rate of about 4 mL / min; said second dose is co-administered with hyaluronidase at a dose of about 500 U / mL. In some embodiments, the first dose and hyaluronidase (at a dose of about 2000 U / mL) are administered on day 1 and the second dose and hyaluronidase (at a dose of about 500 U / mL) are administered on day 15.

[0180]

[0190] In some embodiments, the disclosure provides a method for reducing cognitive impairment in a subject, the method comprising subcutaneously administering to the subject a first dose and a second dose; (a) a first dose comprises about 3400 mg of a brain-targeting antibody or antigen-binding fragment thereof, administered in an injection volume of 20 mL at a flow rate of about 4 mL / min; said first dose is co-administered with recombinant human hyaluronidase at a dose of about 2000 U / mL; (b) a second dose comprising about 6800 mg of a brain-targeting antibody or antigen-binding fragment thereof administered in an injection volume of 40 mL at a flow rate of about 4 mL / min; said second dose is co-administered with recombinant human hyaluronidase at a dose of about 500 U / mL. In some embodiments, the first dose and recombinant human hyaluronidase (at a dose of about 2000 U / mL) are administered on day 1 and the second dose and recombinant human hyaluronidase (at a dose of about 500 U / mL) are administered on day 15.

[0181]

[0191] In some embodiments, the disclosure provides a method for reducing cognitive impairment in a subject, the method comprising subcutaneously administering to the subject a composition comprising about 6800 mg of a brain-targeting antibody or antigen-binding fragment thereof administered at a flow rate of about 4 mL / min in an injection volume of about 40 mL and a permeation enhancer at a dose of about 500 U / mL.

[0182]

[0192] In some embodiments, the disclosure provides a method for reducing cognitive impairment in a subject, the method comprising subcutaneously administering to the subject a composition comprising about 6800 mg of a brain-targeting antibody or antigen-binding fragment thereof administered at a flow rate of about 4 mL / min in an injection volume of about 40 mL and hyaluronidase at a dose of about 500 U / mL.

[0183]

[0193] In some embodiments, the disclosure provides a method for reducing cognitive impairment in a subject, the method comprising subcutaneously administering to the subject a composition comprising about 6800 mg of a brain-targeting antibody or antigen-binding fragment thereof administered at a flow rate of about 4 mL / min in an injection volume of about 40 mL and recombinant human hyaluronidase at a dose of about 500 U / mL.

[0184]

[0194] In some embodiments, the disclosure provides a method for slowing the progression of cognitive impairment in a subject, the method comprising subcutaneously administering to the subject a first dose and a second dose, where (a) the first dose comprises about 1700 mg of a brain-targeting antibody or antigen-binding fragment thereof and is administered in an injection volume of 10 mL at a flow rate of about 2 mL / min; (b) the second dose comprises about 3400 mg of a brain-targeting antibody or antigen-binding fragment thereof and is administered in an injection volume of 20 mL at a flow rate of about 2 mL / min. In some embodiments, the first dose is administered on day 1 and the second dose is administered on day 15.

[0185]

[0195] In some embodiments, the disclosure provides a method for delaying progression of cognitive impairment in a subject, the method comprising subcutaneously administering to the subject a first dose and a second dose; (a) a first dose comprises about 3400 mg of a brain-targeting antibody or antigen-binding fragment thereof and is administered in an injection volume of 20 mL at a flow rate of about 4 mL / min; said first dose is co-administered with a permeation enhancer at a dose of about 2000 U / mL; (b) a second dose comprising about 6800 mg of the brain-targeting antibody or antigen-binding fragment thereof administered in a 40 mL injection volume at a flow rate of about 4 mL / min; said second dose is co-administered with a permeation enhancer at a dose of about 1000 U / mL. In some embodiments, the first dose and the permeation enhancer (at a dose of about 2000 U / mL) are administered on day 1, and the second dose and the permeation enhancer (at a dose of about 1000 U / mL) are administered on day 15.

[0186]

[0196] In some embodiments, the disclosure provides a method for delaying progression of cognitive impairment in a subject, the method comprising subcutaneously administering to the subject a first dose and a second dose; (a) a first dose comprises about 3400 mg of a brain-targeting antibody or antigen-binding fragment thereof and is administered in an injection volume of 20 mL at a flow rate of about 4 mL / min; said first dose is co-administered with hyaluronidase at a dose of about 2000 U / mL; (b) a second dose comprising about 6800 mg of a brain-targeting antibody or antigen-binding fragment thereof administered in an injection volume of 40 mL at a flow rate of about 4 mL / min; said second dose is co-administered with hyaluronidase at a dose of about 1000 U / mL. In some embodiments, the first dose and hyaluronidase (at a dose of about 2000 U / mL) are administered on day 1 and the second dose and hyaluronidase (at a dose of about 1000 U / mL) are administered on day 15.

[0187]

[0197] In some embodiments, the disclosure provides a method for delaying progression of cognitive impairment in a subject, the method comprising subcutaneously administering to the subject a first dose and a second dose; (a) a first dose comprises about 3400 mg of a brain-targeting antibody or antigen-binding fragment thereof, administered in an injection volume of 20 mL at a flow rate of about 4 mL / min; said first dose is co-administered with recombinant human hyaluronidase at a dose of about 2000 U / mL; (b) a second dose comprising about 6800 mg of a brain-targeting antibody or antigen-binding fragment thereof administered in an injection volume of 40 mL at a flow rate of about 4 mL / min; said second dose is co-administered with recombinant human hyaluronidase at a dose of about 1000 U / mL. In some embodiments, the first dose and recombinant human hyaluronidase (at a dose of about 2000 U / mL) are administered on day 1 and the second dose and recombinant human hyaluronidase (at a dose of about 1000 U / mL) are administered on day 15.

[0188]

[0198] In some embodiments, the disclosure provides a method for delaying the progression of cognitive impairment in a subject, the method comprising subcutaneously administering to the subject a first dose and a second dose, where (a) the first dose comprises about 1700 mg of a brain-targeting antibody or antigen-binding fragment thereof and is administered in an injection volume of 10 mL at a flow rate of about 4 mL / min; (b) the second dose comprises about 3400 mg of a brain-targeting antibody or antigen-binding fragment thereof and is administered in an injection volume of 40 mL at a flow rate of about 4 mL / min. In some embodiments, the first dose is administered on day 1 and the second dose is administered on day 15.

[0189]

[0199] In some embodiments, the disclosure provides a method for delaying progression of cognitive impairment in a subject, the method comprising subcutaneously administering to the subject a first dose and a second dose; (a) the first dose comprises about 3400 mg of a brain-targeting antibody or antigen-binding fragment thereof and is administered in an injection volume of 20 mL at a flow rate of about 4 mL / min; (b) a second dose comprising about 6800 mg of the brain-targeting antibody or antigen-binding fragment thereof administered in an injection volume of 40 mL at a flow rate of about 4 mL / min; said second dose is co-administered with a permeation enhancer at a dose of about 500 U / mL. In some embodiments, the first dose is administered on day 1 and the second dose and the permeation enhancer are administered on day 15.

[0190]

[0200] In some embodiments, the disclosure provides a method for delaying progression of cognitive impairment in a subject, the method comprising subcutaneously administering to the subject a first dose and a second dose; (a) the first dose comprises about 3400 mg of a brain-targeting antibody or antigen-binding fragment thereof and is administered in an injection volume of 20 mL at a flow rate of about 4 mL / min; (b) a second dose comprising about 6800 mg of a brain-targeting antibody or antigen-binding fragment thereof administered in an injection volume of 40 mL at a flow rate of about 4 mL / min; said second dose is co-administered with hyaluronidase at a dose of about 500 U / mL. In some embodiments, the first dose is administered on day 1 and the second dose and hyaluronidase are administered on day 15.

[0191]

[0201] In some embodiments, the disclosure provides a method for delaying progression of cognitive impairment in a subject, the method comprising subcutaneously administering to the subject a first dose and a second dose; (a) the first dose comprises about 3400 mg of a brain-targeting antibody or antigen-binding fragment thereof and is administered in an injection volume of 20 mL at a flow rate of about 4 mL / min; (b) a second dose comprising about 6800 mg of a brain-targeting antibody or antigen-binding fragment thereof administered in an injection volume of 40 mL at a flow rate of about 4 mL / min; said second dose is co-administered with recombinant human hyaluronidase at a dose of about 500 U / mL. In some embodiments, the first dose is administered on day 1 and the second dose and recombinant human hyaluronidase are administered on day 15.

[0192]

[0202] In some embodiments, the disclosure provides a method for delaying progression of cognitive impairment in a subject, the method comprising subcutaneously administering to the subject a first dose and a second dose; (a) a first dose comprises about 3400 mg of a brain-targeting antibody or antigen-binding fragment thereof and is administered in an injection volume of 20 mL at a flow rate of about 4 mL / min; said first dose is co-administered with a permeation enhancer at a dose of about 2000 U / mL; (b) a second dose comprising about 6800 mg of the brain-targeting antibody or antigen-binding fragment thereof administered in a 40 mL injection volume at a flow rate of about 4 mL / min; said second dose is co-administered with a permeation enhancer at a dose of about 500 U / mL. In some embodiments, the first dose and the permeation enhancer (at a dose of about 2000 U / mL) are administered on day 1, and the second dose and the permeation enhancer (at a dose of about 500 U / mL) are administered on day 15.

[0193]

[0203] In some embodiments, the disclosure provides a method for delaying progression of cognitive impairment in a subject, the method comprising subcutaneously administering to the subject a first dose and a second dose; (a) a first dose comprises about 3400 mg of a brain-targeting antibody or antigen-binding fragment thereof and is administered in an injection volume of 20 mL at a flow rate of about 4 mL / min; said first dose is co-administered with hyaluronidase at a dose of about 2000 U / mL; (b) a second dose comprising about 6800 mg of a brain-targeting antibody or antigen-binding fragment thereof administered in an injection volume of 40 mL at a flow rate of about 4 mL / min; said second dose is co-administered with hyaluronidase at a dose of about 500 U / mL. In some embodiments, the first dose and hyaluronidase (at a dose of about 2000 U / mL) are administered on day 1 and the second dose and hyaluronidase (at a dose of about 500 U / mL) are administered on day 15.

[0194]

[0204] In some embodiments, the disclosure provides a method for delaying progression of cognitive impairment in a subject, the method comprising subcutaneously administering to the subject a first dose and a second dose; (a) a first dose comprises about 3400 mg of a brain-targeting antibody or antigen-binding fragment thereof, administered in an injection volume of 20 mL at a flow rate of about 4 mL / min; said first dose is co-administered with recombinant human hyaluronidase at a dose of about 2000 U / mL; (b) a second dose comprising about 6800 mg of a brain-targeting antibody or antigen-binding fragment thereof administered in an injection volume of 40 mL at a flow rate of about 4 mL / min; said second dose is co-administered with recombinant human hyaluronidase at a dose of about 500 U / mL. In some embodiments, the first dose and recombinant human hyaluronidase (at a dose of about 2000 U / mL) are administered on day 1 and the second dose and recombinant human hyaluronidase (at a dose of about 500 U / mL) are administered on day 15.

[0195]

[0205] In some embodiments, the disclosure provides a method for slowing the progression of cognitive impairment in a subject, the method comprising subcutaneously administering to the subject a composition comprising about 6800 mg of a brain-targeting antibody or antigen-binding fragment thereof administered at a flow rate of about 4 mL / min in an injection volume of about 40 mL, and a permeation enhancer at a dose of about 500 U / mL.

[0196]

[0206] In some embodiments, the disclosure provides a method for slowing the progression of cognitive impairment in a subject, the method comprising subcutaneously administering to the subject a composition comprising about 6800 mg of a brain-targeting antibody or antigen-binding fragment thereof administered at a flow rate of about 4 mL / min in an injection volume of about 40 mL, and hyaluronidase at a dose of about 500 U / mL.

[0197]

[0207] In some embodiments, the disclosure provides a method for slowing the progression of cognitive impairment in a subject, the method comprising subcutaneously administering to the subject a composition comprising about 6800 mg of a brain-targeting antibody or antigen-binding fragment thereof administered at a flow rate of about 4 mL / min in an injection volume of about 40 mL and recombinant human hyaluronidase at a dose of about 500 U / mL.

[0198]

[0208] In some embodiments, the disclosure provides a method of slowing progression in a subject diagnosed with early or mild-to-moderate Alzheimer's disease (AD), the method comprising subcutaneously administering to the subject a first dose and a second dose, where (a) the first dose comprises about 1700 mg of a brain-targeting antibody or antigen-binding fragment thereof and is administered in an injection volume of 10 mL at a flow rate of about 2 mL / min; (b) the second dose comprises about 3400 mg of a brain-targeting antibody or antigen-binding fragment thereof and is administered in an injection volume of 20 mL at a flow rate of about 2 mL / min. In some embodiments, the first dose is administered on day 1 and the second dose is administered on day 15.

[0199]

[0209] In some embodiments, the disclosure provides a method for delaying progression in a subject diagnosed with early or mild-to-moderate Alzheimer's disease (AD), the method comprising subcutaneously administering to the subject a first dose and a second dose; (a) a first dose comprises about 3400 mg of a brain-targeting antibody or antigen-binding fragment thereof and is administered in an injection volume of 20 mL at a flow rate of about 4 mL / min; said first dose is co-administered with a permeation enhancer at a dose of about 2000 U / mL; (b) a second dose comprising about 6800 mg of a brain-targeting antibody or antigen-binding fragment thereof administered in an injection volume of 40 mL at a flow rate of about 4 mL / min; said second dose is co-administered with a permeation enhancer at a dose of about 1000 U / mL. In some embodiments, the first dose and recombinant human hyaluronidase (at a dose of about 2000 U / mL) are administered on day 1 and the second dose and recombinant human hyaluronidase (at a dose of about 1000 U / mL) are administered on day 15.

[0200]

[0210] In some embodiments, the disclosure provides a method for delaying progression in a subject diagnosed with early or mild-to-moderate Alzheimer's disease (AD), the method comprising subcutaneously administering to the subject a first dose and a second dose; (a) a first dose comprises about 3400 mg of a brain-targeting antibody or antigen-binding fragment thereof and is administered in an injection volume of 20 mL at a flow rate of about 4 mL / min; said first dose is co-administered with hyaluronidase at a dose of about 2000 U / mL; (b) a second dose comprising about 6800 mg of a brain-targeting antibody or antigen-binding fragment thereof administered in an injection volume of 40 mL at a flow rate of about 4 mL / min; said second dose is co-administered with hyaluronidase at a dose of about 1000 U / mL. In some embodiments, the first dose and hyaluronidase (at a dose of about 2000 U / mL) are administered on day 1 and the second dose and hyaluronidase (at a dose of about 1000 U / mL) are administered on day 15.

[0201]

[0211] In some embodiments, the disclosure provides a method for delaying progression in a subject diagnosed with early or mild-to-moderate Alzheimer's disease (AD), the method comprising subcutaneously administering to the subject a first dose and a second dose; (a) a first dose comprises about 3400 mg of a brain-targeting antibody or antigen-binding fragment thereof, administered in an injection volume of 20 mL at a flow rate of about 4 mL / min; said first dose is co-administered with recombinant human hyaluronidase at a dose of about 2000 U / mL; (b) a second dose comprising about 6800 mg of a brain-targeting antibody or antigen-binding fragment thereof administered in an injection volume of 40 mL at a flow rate of about 4 mL / min; said second dose is co-administered with recombinant human hyaluronidase at a dose of about 1000 U / mL. In some embodiments, the first dose and recombinant human hyaluronidase (at a dose of about 2000 U / mL) are administered on day 1 and the second dose and recombinant human hyaluronidase (at a dose of about 1000 U / mL) are administered on day 15.

[0202]

[0212] In some embodiments, the disclosure provides a method of slowing progression in a subject diagnosed with early or mild-to-moderate Alzheimer's disease (AD), the method comprising subcutaneously administering to the subject a first dose and a second dose, where (a) the first dose comprises about 1700 mg of a brain-targeting antibody or antigen-binding fragment thereof and is administered in an injection volume of 10 mL at a flow rate of about 4 mL / min; (b) the second dose comprises about 3400 mg of a brain-targeting antibody or antigen-binding fragment thereof and is administered in an injection volume of 40 mL at a flow rate of about 4 mL / min. In some embodiments, the first dose is administered on day 1 and the second dose is administered on day 15.

[0203]

[0213] In some embodiments, the disclosure provides a method of slowing progression in a subject diagnosed with early or mild-to-moderate Alzheimer's disease (AD), the method comprising subcutaneously administering to the subject a first dose and a second dose; (a) the first dose comprises about 3400 mg of a brain-targeting antibody or antigen-binding fragment thereof and is administered in an injection volume of 20 mL at a flow rate of about 4 mL / min; (b) a second dose comprising about 6800 mg of the brain-targeting antibody or antigen-binding fragment thereof administered in an injection volume of 40 mL at a flow rate of about 4 mL / min; said second dose is co-administered with a permeation enhancer at a dose of about 500 U / mL. In some embodiments, the first dose is administered on day 1 and the second dose and the permeation enhancer are administered on day 15.

[0204]

[0214] In some embodiments, the disclosure provides a method of slowing progression in a subject diagnosed with early or mild-to-moderate Alzheimer's disease (AD), the method comprising subcutaneously administering to the subject a first dose and a second dose; (a) the first dose comprises about 3400 mg of a brain-targeting antibody or antigen-binding fragment thereof and is administered in an injection volume of 20 mL at a flow rate of about 4 mL / min; (b) a second dose comprising about 6800 mg of a brain-targeting antibody or antigen-binding fragment thereof administered in an injection volume of 40 mL at a flow rate of about 4 mL / min; said second dose is co-administered with hyaluronidase at a dose of about 500 U / mL. In some embodiments, the first dose is administered on day 1 and the second dose and hyaluronidase are administered on day 15.

[0205]

[0215] In some embodiments, the disclosure provides a method of slowing progression in a subject diagnosed with early or mild-to-moderate Alzheimer's disease (AD), the method comprising subcutaneously administering to the subject a first dose and a second dose; (a) the first dose comprises about 3400 mg of a brain-targeting antibody or antigen-binding fragment thereof and is administered in an injection volume of 20 mL at a flow rate of about 4 mL / min; (b) a second dose comprising about 6800 mg of a brain-targeting antibody or antigen-binding fragment thereof administered in an injection volume of 40 mL at a flow rate of about 4 mL / min; said second dose is co-administered with recombinant human hyaluronidase at a dose of about 500 U / mL. In some embodiments, the first dose is administered on day 1 and the second dose and recombinant human hyaluronidase are administered on day 15.

[0206]

[0216] In some embodiments, the disclosure provides a method for delaying progression in a subject diagnosed with early or mild-to-moderate Alzheimer's disease (AD), the method comprising subcutaneously administering to the subject a first dose and a second dose; (a) a first dose comprises about 3400 mg of a brain-targeting antibody or antigen-binding fragment thereof and is administered in an injection volume of 20 mL at a flow rate of about 4 mL / min; said first dose is co-administered with a permeation enhancer at a dose of about 2000 U / mL; (b) a second dose comprising about 6800 mg of the brain-targeting antibody or antigen-binding fragment thereof administered in a 40 mL injection volume at a flow rate of about 4 mL / min; said second dose is co-administered with a permeation enhancer at a dose of about 500 U / mL. In some embodiments, the first dose and the permeation enhancer (at a dose of about 2000 U / mL) are administered on day 1, and the second dose and the permeation enhancer (at a dose of about 500 U / mL) are administered on day 15.

[0207]

[0217] In some embodiments, the disclosure provides a method for delaying progression in a subject diagnosed with early or mild-to-moderate Alzheimer's disease (AD), the method comprising subcutaneously administering to the subject a first dose and a second dose; (a) a first dose comprises about 3400 mg of a brain-targeting antibody or antigen-binding fragment thereof and is administered in an injection volume of 20 mL at a flow rate of about 4 mL / min; said first dose is co-administered with hyaluronidase at a dose of about 2000 U / mL; (b) a second dose comprising about 6800 mg of a brain-targeting antibody or antigen-binding fragment thereof administered in an injection volume of 40 mL at a flow rate of about 4 mL / min; said second dose is co-administered with hyaluronidase at a dose of about 500 U / mL. In some embodiments, the first dose and hyaluronidase (at a dose of about 2000 U / mL) are administered on day 1 and the second dose and hyaluronidase (at a dose of about 500 U / mL) are administered on day 15.

[0208]

[0218] In some embodiments, the disclosure provides a method for delaying progression in a subject diagnosed with early or mild-to-moderate Alzheimer's disease (AD), the method comprising subcutaneously administering to the subject a first dose and a second dose; (a) a first dose comprises about 3400 mg of a brain-targeting antibody or antigen-binding fragment thereof, administered in an injection volume of 20 mL at a flow rate of about 4 mL / min; said first dose is co-administered with recombinant human hyaluronidase at a dose of about 2000 U / mL; (b) a second dose comprising about 6800 mg of a brain-targeting antibody or antigen-binding fragment thereof administered in an injection volume of 40 mL at a flow rate of about 4 mL / min; said second dose is co-administered with recombinant human hyaluronidase at a dose of about 500 U / mL. In some embodiments, the first dose and recombinant human hyaluronidase (at a dose of about 2000 U / mL) are administered on day 1 and the second dose and recombinant human hyaluronidase (at a dose of about 500 U / mL) are administered on day 15.

[0209]

[0219] In some embodiments, the disclosure provides a method of slowing progression in a subject diagnosed with early or mild-to-moderate Alzheimer's disease (AD), the method comprising subcutaneously administering to the subject a composition comprising about 6800 mg of a brain-targeting antibody or antigen-binding fragment thereof administered at a flow rate of about 4 mL / min in an injection volume of about 40 mL, and a permeation enhancer at a dose of about 500 U / mL.

[0210]

[0220] In some embodiments, the disclosure provides a method of slowing progression in a subject diagnosed with early or mild-to-moderate Alzheimer's disease (AD), the method comprising subcutaneously administering to the subject a composition comprising about 6800 mg of a brain-targeting antibody or antigen-binding fragment thereof administered at a flow rate of about 4 mL / min in an injection volume of about 40 mL, and hyaluronidase at a dose of about 500 U / mL.

[0211]

[0221] In some embodiments, the disclosure provides a method of slowing progression in a subject diagnosed with early or mild-to-moderate Alzheimer's disease (AD), the method comprising subcutaneously administering to the subject a composition comprising about 6800 mg of a brain-targeting antibody or antigen-binding fragment thereof administered at a flow rate of about 4 mL / min in an injection volume of about 40 mL, and recombinant human hyaluronidase at a dose of about 500 U / mL.

[0212]

[0222] In some embodiments, the disclosure provides a method of treating early or mild-to-moderate AD without increasing the risk of adverse events, the method comprising subcutaneously administering to a subject a first dose and a second dose, where (a) the first dose comprises about 1700 mg of a brain-targeting antibody or antigen-binding fragment thereof and is administered in an injection volume of 10 mL at a flow rate of about 2 mL / min; (b) the second dose comprises about 3400 mg of a brain-targeting antibody or antigen-binding fragment thereof and is administered in an injection volume of 20 mL at a flow rate of about 2 mL / min. In some embodiments, the first dose is administered on day 1 and the second dose is administered on day 15.

[0213]

[0223] In some embodiments, the disclosure provides a method of treating early or mild-to-moderate AD without increasing the risk of adverse events, the method comprising subcutaneously administering to a subject a first dose and a second dose; (a) a first dose comprises about 3400 mg of a brain-targeting antibody or antigen-binding fragment thereof and is administered in an injection volume of 20 mL at a flow rate of about 4 mL / min; said first dose is co-administered with a permeation enhancer at a dose of about 2000 U / mL; (b) a second dose comprising about 6800 mg of the brain-targeting antibody or antigen-binding fragment thereof administered in a 40 mL injection volume at a flow rate of about 4 mL / min; said second dose is co-administered with a permeation enhancer at a dose of about 1000 U / mL. In some embodiments, the first dose and the permeation enhancer (at a dose of about 2000 U / mL) are administered on day 1, and the second dose and the permeation enhancer (at a dose of about 1000 U / mL) are administered on day 15.

[0214]

[0224] In some embodiments, the disclosure provides a method of treating early or mild-to-moderate AD without increasing the risk of adverse events, the method comprising subcutaneously administering to a subject a first dose and a second dose; (a) a first dose comprises about 3400 mg of a brain-targeting antibody or antigen-binding fragment thereof and is administered in an injection volume of 20 mL at a flow rate of about 4 mL / min; said first dose is co-administered with hyaluronidase at a dose of about 2000 U / mL; (b) a second dose comprising about 6800 mg of a brain-targeting antibody or antigen-binding fragment thereof administered in an injection volume of 40 mL at a flow rate of about 4 mL / min; said second dose is co-administered with hyaluronidase at a dose of about 1000 U / mL. In some embodiments, the first dose and hyaluronidase (at a dose of about 2000 U / mL) are administered on day 1 and the second dose and hyaluronidase (at a dose of about 1000 U / mL) are administered on day 15.

[0215]

[0225] In some embodiments, the disclosure provides a method of treating early or mild-to-moderate AD without increasing the risk of adverse events, the method comprising subcutaneously administering to a subject a first dose and a second dose; (a) a first dose comprises about 3400 mg of a brain-targeting antibody or antigen-binding fragment thereof, administered in an injection volume of 20 mL at a flow rate of about 4 mL / min; said first dose is co-administered with recombinant human hyaluronidase at a dose of about 2000 U / mL; (b) a second dose comprising about 6800 mg of a brain-targeting antibody or antigen-binding fragment thereof administered in an injection volume of 40 mL at a flow rate of about 4 mL / min; said second dose is co-administered with recombinant human hyaluronidase at a dose of about 1000 U / mL. In some embodiments, the first dose and recombinant human hyaluronidase (at a dose of about 2000 U / mL) are administered on day 1 and the second dose and recombinant human hyaluronidase (at a dose of about 1000 U / mL) are administered on day 15.

[0216]

[0226] In some embodiments, the disclosure provides a method of treating early or mild-to-moderate AD without increasing the risk of adverse events, the method comprising subcutaneously administering to a subject a first dose and a second dose, where (a) the first dose comprises about 1700 mg of a brain-targeting antibody or antigen-binding fragment thereof and is administered in an injection volume of 10 mL at a flow rate of about 4 mL / min; (b) the second dose comprises about 3400 mg of a brain-targeting antibody or antigen-binding fragment thereof and is administered in an injection volume of 40 mL at a flow rate of about 4 mL / min. In some embodiments, the first dose is administered on day 1 and the second dose is administered on day 15.

[0217]

[0227] In some embodiments, the disclosure provides a method of treating mild to moderate AD without increasing the risk of adverse events, the method comprising subcutaneously administering to a subject a first dose and a second dose; (a) the first dose comprises about 3400 mg of a brain-targeting antibody or antigen-binding fragment thereof and is administered in an injection volume of 20 mL at a flow rate of about 4 mL / min; (b) a second dose comprising about 6800 mg of the brain-targeting antibody or antigen-binding fragment thereof administered in an injection volume of 40 mL at a flow rate of about 4 mL / min; said second dose is co-administered with a permeation enhancer at a dose of about 500 U / mL. In some embodiments, the first dose is administered on day 1 and the second dose and the permeation enhancer are administered on day 15.

[0218]

[0228] In some embodiments, the disclosure provides a method of treating mild to moderate AD without increasing the risk of adverse events, the method comprising subcutaneously administering to a subject a first dose and a second dose; (a) the first dose comprises about 3400 mg of a brain-targeting antibody or antigen-binding fragment thereof and is administered in an injection volume of 20 mL at a flow rate of about 4 mL / min; (b) a second dose comprising about 6800 mg of a brain-targeting antibody or antigen-binding fragment thereof administered in an injection volume of 40 mL at a flow rate of about 4 mL / min; said second dose is co-administered with hyaluronidase at a dose of about 500 U / mL. In some embodiments, the first dose is administered on day 1 and the second dose and hyaluronidase are administered on day 15.

[0219]

[0229] In some embodiments, the disclosure provides a method of treating mild to moderate AD without increasing the risk of adverse events, the method comprising subcutaneously administering to a subject a first dose and a second dose; (a) the first dose comprises about 3400 mg of a brain-targeting antibody or antigen-binding fragment thereof and is administered in an injection volume of 20 mL at a flow rate of about 4 mL / min; (b) a second dose comprising about 6800 mg of a brain-targeting antibody or antigen-binding fragment thereof administered in an injection volume of 40 mL at a flow rate of about 4 mL / min; said second dose is co-administered with recombinant human hyaluronidase at a dose of about 500 U / mL. In some embodiments, the first dose is administered on day 1 and the second dose and recombinant human hyaluronidase are administered on day 15.

[0220]

[0230] In some embodiments, the disclosure provides a method of treating early or mild-to-moderate AD without increasing the risk of adverse events, the method comprising subcutaneously administering to a subject a first dose and a second dose; (a) a first dose comprises about 3400 mg of a brain-targeting antibody or antigen-binding fragment thereof and is administered in an injection volume of 20 mL at a flow rate of about 4 mL / min; said first dose is co-administered with a permeation enhancer at a dose of about 2000 U / mL; (b) a second dose comprising about 6800 mg of the brain-targeting antibody or antigen-binding fragment thereof administered in a 40 mL injection volume at a flow rate of about 4 mL / min; said second dose is co-administered with a permeation enhancer at a dose of about 500 U / mL. In some embodiments, the first dose and the permeation enhancer (at a dose of about 2000 U / mL) are administered on day 1, and the second dose and the permeation enhancer (at a dose of about 500 U / mL) are administered on day 15.

[0221]

[0231] In some embodiments, the disclosure provides a method of treating early or mild-to-moderate AD without increasing the risk of adverse events, the method comprising subcutaneously administering to a subject a first dose and a second dose; (a) a first dose comprises about 3400 mg of a brain-targeting antibody or antigen-binding fragment thereof and is administered in an injection volume of 20 mL at a flow rate of about 4 mL / min; said first dose is co-administered with hyaluronidase at a dose of about 2000 U / mL; (b) a second dose comprising about 6800 mg of a brain-targeting antibody or antigen-binding fragment thereof administered in an injection volume of 40 mL at a flow rate of about 4 mL / min; said second dose is co-administered with hyaluronidase at a dose of about 500 U / mL. In some embodiments, the first dose and hyaluronidase (at a dose of about 2000 U / mL) are administered on day 1 and the second dose and hyaluronidase (at a dose of about 500 U / mL) are administered on day 15.

[0222]

[0232] In some embodiments, the disclosure provides a method of treating early or mild-to-moderate AD without increasing the risk of adverse events, the method comprising subcutaneously administering to a subject a first dose and a second dose; (a) a first dose comprises about 3400 mg of a brain-targeting antibody or antigen-binding fragment thereof, administered in an injection volume of 20 mL at a flow rate of about 4 mL / min; said first dose is co-administered with recombinant human hyaluronidase at a dose of about 2000 U / mL; (b) a second dose comprising about 6800 mg of a brain-targeting antibody or antigen-binding fragment thereof administered in an injection volume of 40 mL at a flow rate of about 4 mL / min; said second dose is co-administered with recombinant human hyaluronidase at a dose of about 500 U / mL. In some embodiments, the first dose and recombinant human hyaluronidase (at a dose of about 2000 U / mL) are administered on day 1 and the second dose and recombinant human hyaluronidase (at a dose of about 500 U / mL) are administered on day 15.

[0223]

[0233] In some embodiments, the disclosure provides a method of treating early or mild-to-moderate AD without increasing the risk of adverse events, the method comprising subcutaneously administering to a subject a composition comprising about 6800 mg of a brain-targeting antibody or antigen-binding fragment thereof administered at a flow rate of about 4 mL / min in an injection volume of about 40 mL, and a permeation enhancer at a dose of about 500 U / mL.

[0224]

[0234] In some embodiments, the disclosure provides a method of treating early or mild-to-moderate AD without increasing the risk of adverse events, the method comprising subcutaneously administering to a subject a composition comprising about 6800 mg of a brain-targeting antibody or antigen-binding fragment thereof administered at a flow rate of about 4 mL / min in an injection volume of about 40 mL, and hyaluronidase at a dose of about 500 U / mL.

[0225]

[0235] In some embodiments, the disclosure provides a method of treating early or mild-to-moderate AD without increasing the risk of adverse events, the method comprising subcutaneously administering to a subject a composition comprising about 6800 mg of a brain-targeting antibody or antigen-binding fragment thereof administered at a flow rate of about 4 mL / min in an injection volume of about 40 mL, and recombinant human hyaluronidase at a dose of about 500 U / mL.

[0226]

[0236] In some embodiments, the disclosure provides a method of delaying clinical deterioration in a patient diagnosed with early or mild-to-moderate Alzheimer's disease (AD), the method comprising subcutaneously administering to the subject a first dose and a second dose, where (a) the first dose comprises about 1700 mg of a brain-targeting antibody or antigen-binding fragment thereof and is administered in an injection volume of 10 mL at a flow rate of about 2 mL / min; (b) the second dose comprises about 3400 mg of a brain-targeting antibody or antigen-binding fragment thereof and is administered in an injection volume of 20 mL at a flow rate of about 2 mL / min. In some embodiments, the first dose is administered on day 1 and the second dose is administered on day 15.

[0227]

[0237] In some embodiments, the disclosure provides a method of delaying clinical deterioration in a patient diagnosed with early or mild-to-moderate Alzheimer's disease (AD), the method comprising subcutaneously administering to the subject a first dose and a second dose; (a) a first dose comprises about 3400 mg of a brain-targeting antibody or antigen-binding fragment thereof and is administered in an injection volume of 20 mL at a flow rate of about 4 mL / min; said first dose is co-administered with a permeation enhancer at a dose of about 2000 U / mL; (b) a second dose comprising about 6800 mg of the brain-targeting antibody or antigen-binding fragment thereof administered in a 40 mL injection volume at a flow rate of about 4 mL / min; said second dose is co-administered with a permeation enhancer at a dose of about 1000 U / mL. In some embodiments, the first dose and the permeation enhancer (at a dose of about 2000 U / mL) are administered on day 1, and the second dose and the permeation enhancer (at a dose of about 1000 U / mL) are administered on day 15.

[0228]

[0238] In some embodiments, the disclosure provides a method of delaying clinical deterioration in a patient diagnosed with early or mild-to-moderate Alzheimer's disease (AD), the method comprising subcutaneously administering to the subject a first dose and a second dose; (a) a first dose comprises about 3400 mg of a brain-targeting antibody or antigen-binding fragment thereof and is administered in an injection volume of 20 mL at a flow rate of about 4 mL / min; said first dose is co-administered with hyaluronidase at a dose of about 2000 U / mL; (b) a second dose comprising about 6800 mg of a brain-targeting antibody or antigen-binding fragment thereof administered in an injection volume of 40 mL at a flow rate of about 4 mL / min; said second dose is co-administered with hyaluronidase at a dose of about 1000 U / mL. In some embodiments, the first dose and hyaluronidase (at a dose of about 2000 U / mL) are administered on day 1 and the second dose and hyaluronidase (at a dose of about 1000 U / mL) are administered on day 15.

[0229]

[0239] In some embodiments, the disclosure provides a method of delaying clinical deterioration in a patient diagnosed with early or mild-to-moderate Alzheimer's disease (AD), the method comprising subcutaneously administering to the subject a first dose and a second dose; (a) a first dose comprises about 3400 mg of a brain-targeting antibody or antigen-binding fragment thereof, administered in an injection volume of 20 mL at a flow rate of about 4 mL / min; said first dose is co-administered with recombinant human hyaluronidase at a dose of about 2000 U / mL; (b) a second dose comprising about 6800 mg of a brain-targeting antibody or antigen-binding fragment thereof administered in an injection volume of 40 mL at a flow rate of about 4 mL / min; said second dose is co-administered with recombinant human hyaluronidase at a dose of about 1000 U / mL. In some embodiments, the first dose and recombinant human hyaluronidase (at a dose of about 2000 U / mL) are administered on day 1 and the second dose and recombinant human hyaluronidase (at a dose of about 1000 U / mL) are administered on day 15.

[0230]

[0240] In some embodiments, the disclosure provides a method of delaying clinical deterioration in a patient diagnosed with early or mild-to-moderate Alzheimer's disease (AD), the method comprising subcutaneously administering to the subject a first dose and a second dose, where (a) the first dose comprises about 1700 mg of a brain-targeting antibody or antigen-binding fragment thereof and is administered in an injection volume of 10 mL at a flow rate of about 4 mL / min; (b) the second dose comprises about 3400 mg of a brain-targeting antibody or antigen-binding fragment thereof and is administered in an injection volume of 40 mL at a flow rate of about 4 mL / min. In some embodiments, the first dose is administered on day 1 and the second dose is administered on day 15.

[0231]

[0241] In some embodiments, the disclosure provides a method of delaying clinical deterioration in a patient diagnosed with early or mild-to-moderate Alzheimer's disease (AD), the method comprising subcutaneously administering to the subject a first dose and a second dose; (a) the first dose comprises about 3400 mg of a brain-targeting antibody or antigen-binding fragment thereof and is administered in an injection volume of 20 mL at a flow rate of about 4 mL / min; (b) a second dose comprising about 6800 mg of the brain-targeting antibody or antigen-binding fragment thereof administered in an injection volume of 40 mL at a flow rate of about 4 mL / min; said second dose is co-administered with a permeation enhancer at a dose of about 500 U / mL. In some embodiments, the first dose is administered on day 1 and the second dose and the permeation enhancer are administered on day 15.

[0232]

[0242] In some embodiments, the disclosure provides a method of delaying clinical deterioration in a patient diagnosed with early or mild-to-moderate Alzheimer's disease (AD), the method comprising subcutaneously administering to the subject a first dose and a second dose; (a) the first dose comprises about 3400 mg of a brain-targeting antibody or antigen-binding fragment thereof and is administered in an injection volume of 20 mL at a flow rate of about 4 mL / min; (b) a second dose comprising about 6800 mg of a brain-targeting antibody or antigen-binding fragment thereof administered in an injection volume of 40 mL at a flow rate of about 4 mL / min; said second dose is co-administered with hyaluronidase at a dose of about 500 U / mL. In some embodiments, the first dose is administered on day 1 and the second dose and hyaluronidase are administered on day 15.

[0233]

[0243] In some embodiments, the disclosure provides a method of delaying clinical deterioration in a patient diagnosed with early or mild-to-moderate Alzheimer's disease (AD), the method comprising subcutaneously administering to the subject a first dose and a second dose; (a) the first dose comprises about 3400 mg of a brain-targeting antibody or antigen-binding fragment thereof and is administered in an injection volume of 20 mL at a flow rate of about 4 mL / min; (b) a second dose comprising about 6800 mg of a brain-targeting antibody or antigen-binding fragment thereof administered in an injection volume of 40 mL at a flow rate of about 4 mL / min; said second dose is co-administered with recombinant human hyaluronidase at a dose of about 500 U / mL. In some embodiments, the first dose is administered on day 1 and the second dose and recombinant human hyaluronidase are administered on day 15.

[0234]

[0244] In some embodiments, the disclosure provides a method of delaying clinical deterioration in a patient diagnosed with early or mild-to-moderate Alzheimer's disease (AD), the method comprising subcutaneously administering to the subject a first dose and a second dose; (a) a first dose comprises about 3400 mg of a brain-targeting antibody or antigen-binding fragment thereof and is administered in an injection volume of 20 mL at a flow rate of about 4 mL / min; said first dose is co-administered with a permeation enhancer at a dose of about 2000 U / mL; (b) a second dose comprising about 6800 mg of the brain-targeting antibody or antigen-binding fragment thereof administered in a 40 mL injection volume at a flow rate of about 4 mL / min; said second dose is co-administered with a permeation enhancer at a dose of about 500 U / mL. In some embodiments, the first dose and the permeation enhancer (at a dose of about 2000 U / mL) are administered on day 1, and the second dose and the permeation enhancer (at a dose of about 500 U / mL) are administered on day 15.

[0235]

[0245] In some embodiments, the disclosure provides a method of delaying clinical deterioration in a patient diagnosed with early or mild-to-moderate Alzheimer's disease (AD), the method comprising subcutaneously administering to the subject a first dose and a second dose; (a) a first dose comprises about 3400 mg of a brain-targeting antibody or antigen-binding fragment thereof and is administered in an injection volume of 20 mL at a flow rate of about 4 mL / min; said first dose is co-administered with hyaluronidase at a dose of about 2000 U / mL; (b) a second dose comprising about 6800 mg of a brain-targeting antibody or antigen-binding fragment thereof administered in an injection volume of 40 mL at a flow rate of about 4 mL / min; said second dose is co-administered with hyaluronidase at a dose of about 500 U / mL. In some embodiments, the first dose and hyaluronidase (at a dose of about 2000 U / mL) are administered on day 1 and the second dose and hyaluronidase (at a dose of about 500 U / mL) are administered on day 15.

[0236]

[0246] In some embodiments, the disclosure provides a method of delaying clinical deterioration in a patient diagnosed with early or mild-to-moderate Alzheimer's disease (AD), the method comprising subcutaneously administering to the subject a first dose and a second dose; (a) a first dose comprises about 3400 mg of a brain-targeting antibody or antigen-binding fragment thereof, administered in an injection volume of 20 mL at a flow rate of about 4 mL / min; said first dose is co-administered with recombinant human hyaluronidase at a dose of about 2000 U / mL; (b) a second dose comprising about 6800 mg of a brain-targeting antibody or antigen-binding fragment thereof administered in an injection volume of 40 mL at a flow rate of about 4 mL / min; said second dose is co-administered with recombinant human hyaluronidase at a dose of about 500 U / mL. In some embodiments, the first dose and recombinant human hyaluronidase (at a dose of about 2000 U / mL) are administered on day 1 and the second dose and recombinant human hyaluronidase (at a dose of about 500 U / mL) are administered on day 15.

[0237]

[0247] In some embodiments, the disclosure provides a method of delaying clinical deterioration in a patient diagnosed with early or mild-to-moderate Alzheimer's disease (AD), the method comprising subcutaneously administering to a subject a composition comprising about 6800 mg of a brain-targeting antibody or antigen-binding fragment thereof administered at a flow rate of about 4 mL / min in an injection volume of about 40 mL, and a permeation enhancer at a dose of about 500 U / mL.

[0238]

[0248] In some embodiments, the disclosure provides a method of delaying clinical deterioration in a patient diagnosed with early or mild-to-moderate Alzheimer's disease (AD), the method comprising subcutaneously administering to a subject a composition comprising about 6800 mg of a brain-targeting antibody or antigen-binding fragment thereof administered at a flow rate of about 4 mL / min in an injection volume of about 40 mL, and hyaluronidase at a dose of about 500 U / mL.

[0239]

[0249] In some embodiments, the disclosure provides a method of delaying clinical deterioration in a patient diagnosed with early or mild-to-moderate Alzheimer's disease (AD), the method comprising subcutaneously administering to a subject a composition comprising about 6800 mg of a brain-targeting antibody or antigen-binding fragment thereof administered at a flow rate of about 4 mL / min in an injection volume of about 40 mL, and recombinant human hyaluronidase at a dose of about 500 U / mL.

[0240]

[0250] In any of the foregoing embodiments, the brain-targeting antibody or antigen-binding fragment thereof may be a full-length brain-targeting antibody.

[0241]

[0251] In some embodiments, the brain-targeting antibody or antigen-binding fragment thereof is an anti-amyloid beta antibody or antigen-binding fragment thereof. In some embodiments, the anti-amyloid beta antibody or antigen-binding fragment thereof comprises: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:1; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:2; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:3; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:4; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO:5; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO:6. In some embodiments, the anti-amyloid beta antibody or antigen-binding fragment thereof comprises a VH domain comprising the amino acid sequence of SEQ ID NO:7. In some embodiments, the anti-amyloid beta antibody or antigen-binding fragment thereof comprises a VL domain comprising the amino acid sequence of SEQ ID NO:8. In some embodiments, the anti-amyloid beta antibody or antigen-binding fragment thereof comprises a VH domain comprising the amino acid sequence of SEQ ID NO:7 and a VL domain comprising the amino acid sequence of SEQ ID NO:8. In some embodiments, the anti-amyloid beta antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 9. In some embodiments, the anti-amyloid beta antibody comprises a light chain comprising the amino acid sequence of SEQ ID NO: 10. In some embodiments, the anti-amyloid beta antibody, or antigen-binding fragment thereof, comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 9 and a light chain comprising the amino acid sequence of SEQ ID NO: 10. In some embodiments, the anti-amyloid beta antibody is crenezumab.

[0242]

[0252] In some embodiments, the anti-amyloid beta antibody or antigen-binding fragment thereof is administered at a dose between about 400 mg and about 7500 mg. In some embodiments, the dose of the anti-amyloid beta antibody or antigen-binding fragment thereof is about 600 mg to 7200 mg. In some embodiments, the anti-amyloid beta antibody or antigen-binding fragment thereof is administered at a dose of about 1700 mg, about 3400 mg, or about 6800 mg. In some embodiments, the anti-amyloid beta antibody is administered at a dose between about 400 mg and about 7500 mg. In some embodiments, the dose of the anti-amyloid beta antibody is about 600 mg to about 7200 mg. In some embodiments, the anti-amyloid beta antibody is administered at a dose of about 1700 mg, about 3400 mg, or about 6800 mg. In some embodiments, crenezumab is administered at a dose between about 400 mg and about 7500 mg. In some embodiments, the dose of crenezumab is about 600 mg to 7200 mg. In some embodiments, crenezumab is administered at a dose of about 1700 mg, about 3400 mg, or about 6800 mg.

[0243]

[0253] In some embodiments, the present disclosure provides a method for treating cognitive impairment in a subject, the method comprising subcutaneously administering to the subject a first dose and a second dose, where (a) the first dose comprises about 1700 mg of an anti-amyloid beta antibody or antigen-binding fragment thereof and is administered in an injection volume of 10 mL at a flow rate of about 2 mL / min; (b) the second dose comprises about 3400 mg of an anti-amyloid beta antibody or antigen-binding fragment thereof and is administered in an injection volume of 20 mL at a flow rate of about 2 mL / min. In some embodiments, the first dose is administered on day 1 and the second dose is administered on day 15.

[0244]

[0254] In some embodiments, the disclosure provides a method for treating a cognitive impairment in a subject, the method comprising subcutaneously administering to the subject a first dose and a second dose; (a) a first dose comprises about 3400 mg of an anti-amyloid beta antibody or antigen-binding fragment thereof and is administered in an injection volume of 20 mL at a flow rate of about 4 mL / min; said first dose is co-administered with a permeation enhancer at a dose of about 2000 U / mL; (b) a second dose comprising about 6800 mg of an anti-amyloid beta antibody or antigen-binding fragment thereof administered in an injection volume of 40 mL at a flow rate of about 4 mL / min; said second dose is co-administered with a permeation enhancer at a dose of about 1000 U / mL. In some embodiments, the first dose and the permeation enhancer (at a dose of about 2000 U / mL) are administered on day 1, and the second dose and the permeation enhancer (at a dose of about 1000 U / mL) are administered on day 15.

[0245]

[0255] In some embodiments, the disclosure provides a method for treating a cognitive impairment in a subject, the method comprising subcutaneously administering to the subject a first dose and a second dose; (a) a first dose comprises about 3400 mg of an anti-amyloid beta antibody or antigen-binding fragment thereof and is administered in an injection volume of 20 mL at a flow rate of about 4 mL / min; said first dose is co-administered with hyaluronidase at a dose of about 2000 U / mL; (b) a second dose comprising about 6800 mg of an anti-amyloid beta antibody or antigen-binding fragment thereof administered in an infusion volume of 40 mL at a flow rate of about 4 mL / min; said second dose is co-administered with hyaluronidase at a dose of about 1000 U / mL. In some embodiments, the first dose and hyaluronidase (at a dose of about 2000 U / mL) are administered on day 1 and the second dose and hyaluronidase (at a dose of about 1000 U / mL) are administered on day 15.

[0246]

[0256] In some embodiments, the disclosure provides a method for treating a cognitive impairment in a subject, the method comprising subcutaneously administering to the subject a first dose and a second dose; (a) a first dose comprises about 3400 mg of an anti-amyloid beta antibody or antigen-binding fragment thereof, administered in an injection volume of 20 mL at a flow rate of about 4 mL / min; said first dose is co-administered with recombinant human hyaluronidase at a dose of about 2000 U / mL; (b) a second dose comprising about 6800 mg of an anti-amyloid beta antibody or antigen-binding fragment thereof administered in an infusion volume of 40 mL at a flow rate of about 4 mL / min; said second dose is co-administered with recombinant human hyaluronidase at a dose of about 1000 U / mL. In some embodiments, the first dose and recombinant human hyaluronidase (at a dose of about 2000 U / mL) are administered on day 1 and the second dose and recombinant human hyaluronidase (at a dose of about 1000 U / mL) are administered on day 15.

[0247]

[0257] In some embodiments, the disclosure provides a method for treating cognitive impairment in a subject, the method comprising subcutaneously administering to the subject a first dose and a second dose, where (a) the first dose comprises about 1700 mg of an anti-amyloid beta antibody or antigen-binding fragment thereof and is administered in an injection volume of 10 mL at a flow rate of about 4 mL / min; (b) the second dose comprises about 3400 mg of an anti-amyloid beta antibody or antigen-binding fragment thereof and is administered in an injection volume of 40 mL at a flow rate of about 4 mL / min. In some embodiments, the first dose is administered on day 1 and the second dose is administered on day 15.

[0248]

[0258] In some embodiments, the disclosure provides a method for treating a cognitive impairment in a subject, the method comprising subcutaneously administering to the subject a first dose and a second dose; (a) the first dose comprises about 3400 mg of an anti-amyloid beta antibody or antigen-binding fragment thereof and is administered in an injection volume of 20 mL at a flow rate of about 4 mL / min; (b) a second dose comprising about 6800 mg of an anti-amyloid beta antibody or antigen-binding fragment thereof administered in an infusion volume of 40 mL at a flow rate of about 4 mL / min; said second dose is co-administered with a permeation enhancer at a dose of about 500 U / mL. In some embodiments, the first dose is administered on day 1 and the second dose and the permeation enhancer are administered on day 15.

[0249]

[0259] In some embodiments, the disclosure provides a method for treating a cognitive impairment in a subject, the method comprising subcutaneously administering to the subject a first dose and a second dose; (a) the first dose comprises about 3400 mg of an anti-amyloid beta antibody or antigen-binding fragment thereof and is administered in an injection volume of 20 mL at a flow rate of about 4 mL / min; (b) a second dose comprising about 6800 mg of an anti-amyloid beta antibody or antigen-binding fragment thereof administered in an infusion volume of 40 mL at a flow rate of about 4 mL / min; said second dose is co-administered with hyaluronidase at a dose of about 500 U / mL. In some embodiments, the first dose is administered on day 1 and the second dose and hyaluronidase are administered on day 15.

[0250]

[0260] In some embodiments, the disclosure provides a method for treating a cognitive impairment in a subject, the method comprising subcutaneously administering to the subject a first dose and a second dose; (a) the first dose comprises about 3400 mg of an anti-amyloid beta antibody or antigen-binding fragment thereof and is administered in an injection volume of 20 mL at a flow rate of about 4 mL / min; (b) a second dose comprising about 6800 mg of an anti-amyloid beta antibody or antigen-binding fragment thereof administered in an infusion volume of 40 mL at a flow rate of about 4 mL / min; said second dose is co-administered with recombinant human hyaluronidase at a dose of about 500 U / mL. In some embodiments, the first dose is administered on day 1 and the second dose and recombinant human hyaluronidase are administered on day 15.

[0251]

[0261] In some embodiments, the disclosure provides a method for treating a cognitive impairment in a subject, the method comprising subcutaneously administering to the subject a first dose and a second dose; (a) a first dose comprises about 3400 mg of an anti-amyloid beta antibody or antigen-binding fragment thereof and is administered in an injection volume of 20 mL at a flow rate of about 4 mL / min; said first dose is co-administered with a permeation enhancer at a dose of about 2000 U / mL; (b) a second dose comprising about 6800 mg of an anti-amyloid beta antibody or antigen-binding fragment thereof administered in an injection volume of 40 mL at a flow rate of about 4 mL / min; said second dose is co-administered with a permeation enhancer at a dose of about 500 U / mL. In some embodiments, the first dose and recombinant human hyaluronidase (at a dose of about 2000 U / mL) are administered on day 1 and the second dose and the permeation enhancer (at a dose of about 500 U / mL) are administered on day 15.

[0252]

[0262] In some embodiments, the disclosure provides a method for treating a cognitive impairment in a subject, the method comprising subcutaneously administering to the subject a first dose and a second dose; (a) a first dose comprises about 3400 mg of an anti-amyloid beta antibody or antigen-binding fragment thereof and is administered in an injection volume of 20 mL at a flow rate of about 4 mL / min; said first dose is co-administered with hyaluronidase at a dose of about 2000 U / mL; (b) a second dose comprising about 6800 mg of an anti-amyloid beta antibody or antigen-binding fragment thereof administered in an infusion volume of 40 mL at a flow rate of about 4 mL / min; said second dose is co-administered with hyaluronidase at a dose of about 500 U / mL. In some embodiments, the first dose and hyaluronidase (at a dose of about 2000 U / mL) are administered on day 1 and the second dose and recombinant human hyaluronidase (at a dose of about 500 U / mL) are administered on day 15.

[0253]

[0263] In some embodiments, the disclosure provides a method for treating a cognitive impairment in a subject, the method comprising subcutaneously administering to the subject a first dose and a second dose; (a) a first dose comprises about 3400 mg of an anti-amyloid beta antibody or antigen-binding fragment thereof, administered in an injection volume of 20 mL at a flow rate of about 4 mL / min; said first dose is co-administered with recombinant human hyaluronidase at a dose of about 2000 U / mL; (b) a second dose comprising about 6800 mg of an anti-amyloid beta antibody or antigen-binding fragment thereof administered in an infusion volume of 40 mL at a flow rate of about 4 mL / min; said second dose is co-administered with recombinant human hyaluronidase at a dose of about 500 U / mL. In some embodiments, the first dose and recombinant human hyaluronidase (at a dose of about 2000 U / mL) are administered on day 1 and the second dose and recombinant human hyaluronidase (at a dose of about 500 U / mL) are administered on day 15.

[0254]

[0264] In some embodiments, the disclosure provides a method for treating cognitive impairment in a subject, the method comprising subcutaneously administering to the subject a composition comprising about 6800 mg of an anti-amyloid beta antibody or antigen-binding fragment thereof administered at a flow rate of about 4 mL / min in an injection volume of about 40 mL, and a permeation enhancer at a dose of about 500 U / mL.

[0255]

[0265] In some embodiments, the disclosure provides a method for treating cognitive impairment in a subject, the method comprising subcutaneously administering to the subject a composition comprising about 6800 mg of an anti-amyloid beta antibody or antigen-binding fragment thereof administered at a flow rate of about 4 mL / min in an injection volume of about 40 mL, and hyaluronidase at a dose of about 500 U / mL.

[0256]

[0266] In some embodiments, the disclosure provides a method for treating cognitive impairment in a subject, the method comprising subcutaneously administering to the subject a composition comprising about 6800 mg of an anti-amyloid beta antibody or antigen-binding fragment thereof administered at a flow rate of about 4 mL / min in an injection volume of about 40 mL and recombinant human hyaluronidase at a dose of about 500 U / mL.

[0257]

[0267] In some embodiments, the disclosure provides a method for treating Alzheimer's disease in a subject, the method comprising subcutaneously administering to the subject a first dose and a second dose, where (a) the first dose comprises about 1700 mg of an anti-amyloid beta antibody or antigen-binding fragment thereof and is administered in an injection volume of 10 mL at a flow rate of about 2 mL / min; and (b) the second dose comprises about 3400 mg of an anti-amyloid beta antibody or antigen-binding fragment thereof and is administered in an injection volume of 20 mL at a flow rate of about 2 mL / min. In some embodiments, the first dose is administered on day 1 and the second dose is administered on day 15.

[0258]

[0268] In some embodiments, the disclosure provides a method for treating Alzheimer's disease in a subject, the method comprising subcutaneously administering to the subject a first dose and a second dose; (a) a first dose comprises about 3400 mg of an anti-amyloid beta antibody or antigen-binding fragment thereof and is administered in an injection volume of 20 mL at a flow rate of about 4 mL / min; said first dose is co-administered with a permeation enhancer at a dose of about 2000 U / mL; (b) a second dose comprising about 6800 mg of an anti-amyloid beta antibody or antigen-binding fragment thereof administered in an injection volume of 40 mL at a flow rate of about 4 mL / min; said second dose is co-administered with a permeation enhancer at a dose of about 1000 U / mL. In some embodiments, the first dose and the permeation enhancer (at a dose of about 2000 U / mL) are administered on day 1, and the second dose and the permeation enhancer (at a dose of about 1000 U / mL) are administered on day 15.

[0259]

[0269] In some embodiments, the disclosure provides a method for treating Alzheimer's disease in a subject, the method comprising subcutaneously administering to the subject a first dose and a second dose; (a) a first dose comprises about 3400 mg of an anti-amyloid beta antibody or antigen-binding fragment thereof and is administered in an injection volume of 20 mL at a flow rate of about 4 mL / min; said first dose is co-administered with hyaluronidase at a dose of about 2000 U / mL; (b) a second dose comprising about 6800 mg of an anti-amyloid beta antibody or antigen-binding fragment thereof administered in an infusion volume of 40 mL at a flow rate of about 4 mL / min; said second dose is co-administered with hyaluronidase at a dose of about 1000 U / mL. In some embodiments, the first dose and hyaluronidase (at a dose of about 2000 U / mL) are administered on day 1 and the second dose and hyaluronidase (at a dose of about 1000 U / mL) are administered on day 15.

[0260]

[0270] In some embodiments, the disclosure provides a method for treating Alzheimer's disease in a subject, the method comprising subcutaneously administering to the subject a first dose and a second dose; (a) a first dose comprises about 3400 mg of an anti-amyloid beta antibody or antigen-binding fragment thereof, administered in an injection volume of 20 mL at a flow rate of about 4 mL / min; said first dose is co-administered with recombinant human hyaluronidase at a dose of about 2000 U / mL; (b) a second dose comprising about 6800 mg of an anti-amyloid beta antibody or antigen-binding fragment thereof administered in an infusion volume of 40 mL at a flow rate of about 4 mL / min; said second dose is co-administered with recombinant human hyaluronidase at a dose of about 1000 U / mL. In some embodiments, the first dose and recombinant human hyaluronidase (at a dose of about 2000 U / mL) are administered on day 1 and the second dose and recombinant human hyaluronidase (at a dose of about 1000 U / mL) are administered on day 15.

[0261]

[0271] In some embodiments, the disclosure provides a method for treating Alzheimer's disease in a subject, the method comprising subcutaneously administering to the subject a first dose and a second dose, where (a) the first dose comprises about 1700 mg of an anti-amyloid beta antibody or antigen-binding fragment thereof and is administered in an injection volume of 10 mL at a flow rate of about 4 mL / min; (b) the second dose comprises about 3400 mg of an anti-amyloid beta antibody or antigen-binding fragment thereof and is administered in an injection volume of 40 mL at a flow rate of about 4 mL / min. In some embodiments, the first dose is administered on day 1 and the second dose is administered on day 15.

[0262]

[0272] In some embodiments, the disclosure provides a method for treating Alzheimer's disease in a subject, the method comprising subcutaneously administering to the subject a first dose and a second dose; (a) the first dose comprises about 3400 mg of an anti-amyloid beta antibody or antigen-binding fragment thereof and is administered in an injection volume of 20 mL at a flow rate of about 4 mL / min; (b) a second dose comprising about 6800 mg of an anti-amyloid beta antibody or antigen-binding fragment thereof administered in an infusion volume of 40 mL at a flow rate of about 4 mL / min; said second dose is co-administered with a permeation enhancer at a dose of about 500 U / mL. In some embodiments, the first dose is administered on day 1 and the second dose and the permeation enhancer are administered on day 15.

[0263]

[0273] In some embodiments, the disclosure provides a method for treating Alzheimer's disease in a subject, the method comprising subcutaneously administering to the subject a first dose and a second dose; (a) the first dose comprises about 3400 mg of an anti-amyloid beta antibody or antigen-binding fragment thereof and is administered in an injection volume of 20 mL at a flow rate of about 4 mL / min; (b) a second dose comprising about 6800 mg of an anti-amyloid beta antibody or antigen-binding fragment thereof administered in an infusion volume of 40 mL at a flow rate of about 4 mL / min; said second dose is co-administered with hyaluronidase at a dose of about 500 U / mL. In some embodiments, the first dose is administered on day 1 and the second dose and hyaluronidase are administered on day 15.

[0264]

[0274] In some embodiments, the disclosure provides a method for treating Alzheimer's disease in a subject, the method comprising subcutaneously administering to the subject a first dose and a second dose; (a) the first dose comprises about 3400 mg of an anti-amyloid beta antibody or antigen-binding fragment thereof and is administered in an injection volume of 20 mL at a flow rate of about 4 mL / min; (b) a second dose comprising about 6800 mg of an anti-amyloid beta antibody or antigen-binding fragment thereof administered in an infusion volume of 40 mL at a flow rate of about 4 mL / min; said second dose is co-administered with recombinant human hyaluronidase at a dose of about 500 U / mL. In some embodiments, the first dose is administered on day 1 and the second dose and recombinant human hyaluronidase are administered on day 15.

[0265]

[0275] In some embodiments, the disclosure provides a method for treating Alzheimer's disease in a subject, the method comprising subcutaneously administering to the subject a first dose and a second dose; (a) a first dose comprises about 3400 mg of an anti-amyloid beta antibody or antigen-binding fragment thereof and is administered in an injection volume of 20 mL at a flow rate of about 4 mL / min; said first dose is co-administered with a permeation enhancer at a dose of about 2000 U / mL; (b) a second dose comprising about 6800 mg of an anti-amyloid beta antibody or antigen-binding fragment thereof administered in an infusion volume of 40 mL at a flow rate of about 4 mL / min; said second dose is co-administered with a permeation enhancer at a dose of about 500 U / mL. In some embodiments, the first dose and the permeation enhancer (at a dose of about 2000 U / mL) are administered on day 1, and the second dose and the permeation enhancer (at a dose of about 500 U / mL) are administered on day 15.

[0266]

[0276] In some embodiments, the disclosure provides a method for treating Alzheimer's disease in a subject, the method comprising subcutaneously administering to the subject a first dose and a second dose; (a) a first dose comprises about 3400 mg of an anti-amyloid beta antibody or antigen-binding fragment thereof and is administered in an injection volume of 20 mL at a flow rate of about 4 mL / min; said first dose is co-administered with hyaluronidase at a dose of about 2000 U / mL; (b) a second dose comprising about 6800 mg of an anti-amyloid beta antibody or antigen-binding fragment thereof administered in an infusion volume of 40 mL at a flow rate of about 4 mL / min; said second dose is co-administered with hyaluronidase at a dose of about 500 U / mL. In some embodiments, the first dose and hyaluronidase (at a dose of about 2000 U / mL) are administered on day 1 and the second dose and hyaluronidase (at a dose of about 500 U / mL) are administered on day 15.

[0267]

[0277] In some embodiments, the disclosure provides a method for treating Alzheimer's disease in a subject, the method comprising subcutaneously administering to the subject a first dose and a second dose; (a) a first dose comprises about 3400 mg of an anti-amyloid beta antibody or antigen-binding fragment thereof, administered in an injection volume of 20 mL at a flow rate of about 4 mL / min; said first dose is co-administered with recombinant human hyaluronidase at a dose of about 2000 U / mL; (b) a second dose comprising about 6800 mg of an anti-amyloid beta antibody or antigen-binding fragment thereof administered in an infusion volume of 40 mL at a flow rate of about 4 mL / min; said second dose is co-administered with recombinant human hyaluronidase at a dose of about 500 U / mL. In some embodiments, the first dose and recombinant human hyaluronidase (at a dose of about 2000 U / mL) are administered on day 1 and the second dose and recombinant human hyaluronidase (at a dose of about 500 U / mL) are administered on day 15.

[0268]

[0278] In some embodiments, the disclosure provides a method for treating Alzheimer's disease in a subject, the method comprising subcutaneously administering to the subject a composition comprising about 6800 mg of an anti-amyloid beta antibody or antigen-binding fragment thereof administered at a flow rate of about 4 mL / min in an injection volume of about 40 mL, and a permeation enhancer at a dose of about 500 U / mL.

[0269]

[0279] In some embodiments, the disclosure provides a method for treating Alzheimer's disease in a subject, the method comprising subcutaneously administering to the subject a composition comprising about 6800 mg of an anti-amyloid beta antibody or antigen-binding fragment thereof administered at a flow rate of about 4 mL / min in an injection volume of about 40 mL, and hyaluronidase at a dose of about 500 U / mL.

[0270]

[0280] In some embodiments, the disclosure provides a method for treating Alzheimer's disease in a subject, the method comprising subcutaneously administering to the subject a composition comprising about 6800 mg of an anti-amyloid beta antibody or antigen-binding fragment thereof administered at a flow rate of about 4 mL / min in an injection volume of about 40 mL and recombinant human hyaluronidase at a dose of about 500 U / mL.

[0271]

[0281] In some embodiments, the disclosure provides a method for treating a subject at risk for Alzheimer's disease, the method comprising subcutaneously administering to the subject a first dose and a second dose, where (a) the first dose comprises about 1700 mg of an anti-amyloid beta antibody or antigen-binding fragment thereof and is administered in an injection volume of 10 mL at a flow rate of about 2 mL / min; (b) the second dose comprises about 3400 mg of an anti-amyloid beta antibody or antigen-binding fragment thereof and is administered in an injection volume of 20 mL at a flow rate of about 2 mL / min. In some embodiments, the first dose is administered on day 1 and the second dose is administered on day 15.

[0272]

[0282] In some embodiments, the disclosure provides a method for treating a subject at risk for Alzheimer's disease, the method comprising subcutaneously administering to the subject a first dose and a second dose; (a) a first dose comprises about 3400 mg of an anti-amyloid beta antibody or antigen-binding fragment thereof and is administered in an injection volume of 20 mL at a flow rate of about 4 mL / min; said first dose is co-administered with a permeation enhancer at a dose of about 2000 U / mL; (b) a second dose comprising about 6800 mg of an anti-amyloid beta antibody or antigen-binding fragment thereof administered in an injection volume of 40 mL at a flow rate of about 4 mL / min; said second dose is co-administered with a permeation enhancer at a dose of about 1000 U / mL. In some embodiments, the first dose and the permeation enhancer (at a dose of about 2000 U / mL) are administered on day 1, and the second dose and the permeation enhancer (at a dose of about 1000 U / mL) are administered on day 15.

[0273]

[0283] In some embodiments, the disclosure provides a method for treating a subject at risk for Alzheimer's disease, the method comprising subcutaneously administering to the subject a first dose and a second dose; (a) a first dose comprises about 3400 mg of an anti-amyloid beta antibody or antigen-binding fragment thereof and is administered in an injection volume of 20 mL at a flow rate of about 4 mL / min; said first dose is co-administered with hyaluronidase at a dose of about 2000 U / mL; (b) a second dose comprising about 6800 mg of an anti-amyloid beta antibody or antigen-binding fragment thereof administered in an infusion volume of 40 mL at a flow rate of about 4 mL / min; said second dose is co-administered with hyaluronidase at a dose of about 1000 U / mL. In some embodiments, the first dose and hyaluronidase (at a dose of about 2000 U / mL) are administered on day 1 and the second dose and hyaluronidase (at a dose of about 1000 U / mL) are administered on day 15.

[0274]

[0284] In some embodiments, the disclosure provides a method for treating a subject at risk for Alzheimer's disease, the method comprising subcutaneously administering to the subject a first dose and a second dose; (a) a first dose comprises about 3400 mg of an anti-amyloid beta antibody or antigen-binding fragment thereof, administered in an injection volume of 20 mL at a flow rate of about 4 mL / min; said first dose is co-administered with recombinant human hyaluronidase at a dose of about 2000 U / mL; (b) a second dose comprising about 6800 mg of an anti-amyloid beta antibody or antigen-binding fragment thereof administered in an infusion volume of 40 mL at a flow rate of about 4 mL / min; said second dose is co-administered with recombinant human hyaluronidase at a dose of about 1000 U / mL. In some embodiments, the first dose and recombinant human hyaluronidase (at a dose of about 2000 U / mL) are administered on day 1 and the second dose and recombinant human hyaluronidase (at a dose of about 1000 U / mL) are administered on day 15.

[0275]

[0285] In some embodiments, the disclosure provides a method for treating a subject at risk for Alzheimer's disease, the method comprising subcutaneously administering to the subject a first dose and a second dose, where (a) the first dose comprises about 1700 mg of an anti-amyloid beta antibody or antigen-binding fragment thereof and is administered in an injection volume of 10 mL at a flow rate of about 4 mL / min; (b) the second dose comprises about 3400 mg of an anti-amyloid beta antibody or antigen-binding fragment thereof and is administered in an injection volume of 40 mL at a flow rate of about 4 mL / min. In some embodiments, the first dose is administered on day 1 and the second dose is administered on day 15.

[0276]

[0286] In some embodiments, the disclosure provides a method for treating a subject at risk for Alzheimer's disease, the method comprising subcutaneously administering to the subject a first dose and a second dose; (a) the first dose comprises about 3400 mg of an anti-amyloid beta antibody or antigen-binding fragment thereof and is administered in an injection volume of 20 mL at a flow rate of about 4 mL / min; (b) a second dose comprising about 6800 mg of an anti-amyloid beta antibody or antigen-binding fragment thereof administered in an infusion volume of 40 mL at a flow rate of about 4 mL / min; said second dose is co-administered with a permeation enhancer at a dose of about 500 U / mL. In some embodiments, the first dose is administered on day 1 and the second dose and the permeation enhancer are administered on day 15.

[0277]

[0287] In some embodiments, the disclosure provides a method for treating a subject at risk for Alzheimer's disease, the method comprising subcutaneously administering to the subject a first dose and a second dose; (a) the first dose comprises about 3400 mg of an anti-amyloid beta antibody or antigen-binding fragment thereof and is administered in an injection volume of 20 mL at a flow rate of about 4 mL / min; (b) a second dose comprising about 6800 mg of an anti-amyloid beta antibody or antigen-binding fragment thereof administered in an infusion volume of 40 mL at a flow rate of about 4 mL / min; said second dose is co-administered with hyaluronidase at a dose of about 500 U / mL. In some embodiments, the first dose is administered on day 1 and the second dose and hyaluronidase are administered on day 15.

[0278]

[0288] In some embodiments, the disclosure provides a method for treating a subject at risk for Alzheimer's disease, the method comprising subcutaneously administering to the subject a first dose and a second dose; (a) the first dose comprises about 3400 mg of an anti-amyloid beta antibody or antigen-binding fragment thereof and is administered in an injection volume of 20 mL at a flow rate of about 4 mL / min; (b) a second dose comprising about 6800 mg of an anti-amyloid beta antibody or antigen-binding fragment thereof administered in an infusion volume of 40 mL at a flow rate of about 4 mL / min; said second dose is co-administered with recombinant human hyaluronidase at a dose of about 500 U / mL. In some embodiments, the first dose is administered on day 1 and the second dose and recombinant human hyaluronidase are administered on day 15.

[0279]

[0289] In some embodiments, the disclosure provides a method for treating a subject at risk for Alzheimer's disease, the method comprising subcutaneously administering to the subject a first dose and a second dose; (a) a first dose comprises about 3400 mg of an anti-amyloid beta antibody or antigen-binding fragment thereof and is administered in an injection volume of 20 mL at a flow rate of about 4 mL / min; said first dose is co-administered with a permeation enhancer at a dose of about 2000 U / mL; (b) a second dose comprising about 6800 mg of an anti-amyloid beta antibody or antigen-binding fragment thereof administered in an infusion volume of 40 mL at a flow rate of about 4 mL / min; said second dose is co-administered with a permeation enhancer at a dose of about 500 U / mL. In some embodiments, the first dose and the permeation enhancer (at a dose of about 2000 U / mL) are administered on day 1, and the second dose and the permeation enhancer (at a dose of about 500 U / mL) are administered on day 15.

[0280]

[0290] In some embodiments, the disclosure provides a method for treating a subject at risk for Alzheimer's disease, the method comprising subcutaneously administering to the subject a first dose and a second dose; (a) a first dose comprises about 3400 mg of an anti-amyloid beta antibody or antigen-binding fragment thereof and is administered in an injection volume of 20 mL at a flow rate of about 4 mL / min; said first dose is co-administered with hyaluronidase at a dose of about 2000 U / mL; (b) a second dose comprising about 6800 mg of an anti-amyloid beta antibody or antigen-binding fragment thereof administered in an infusion volume of 40 mL at a flow rate of about 4 mL / min; said second dose is co-administered with hyaluronidase at a dose of about 500 U / mL. In some embodiments, the first dose and hyaluronidase (at a dose of about 2000 U / mL) are administered on day 1 and the second dose and hyaluronidase (at a dose of about 500 U / mL) are administered on day 15.

[0281]

[0291] In some embodiments, the disclosure provides a method for treating a subject at risk for Alzheimer's disease, the method comprising subcutaneously administering to the subject a first dose and a second dose; (a) a first dose comprises about 3400 mg of an anti-amyloid beta antibody or antigen-binding fragment thereof, administered in an injection volume of 20 mL at a flow rate of about 4 mL / min; said first dose is co-administered with recombinant human hyaluronidase at a dose of about 2000 U / mL; (b) a second dose comprising about 6800 mg of an anti-amyloid beta antibody or antigen-binding fragment thereof administered in an infusion volume of 40 mL at a flow rate of about 4 mL / min; said second dose is co-administered with recombinant human hyaluronidase at a dose of about 500 U / mL. In some embodiments, the first dose and recombinant human hyaluronidase (at a dose of about 2000 U / mL) are administered on day 1 and the second dose and recombinant human hyaluronidase (at a dose of about 500 U / mL) are administered on day 15.

[0282]

[0292] In some embodiments, the disclosure provides a method for treating a subject at risk for Alzheimer's disease, the method comprising subcutaneously administering to the subject a composition comprising about 6800 mg of an anti-amyloid beta antibody or antigen-binding fragment thereof administered at a flow rate of about 4 mL / min in an injection volume of about 40 mL, and a permeation enhancer at a dose of about 500 U / mL.

[0283]

[0293] In some embodiments, the disclosure provides a method for treating a subject at risk for Alzheimer's disease, the method comprising subcutaneously administering to the subject a composition comprising about 6800 mg of an anti-amyloid beta antibody or antigen-binding fragment thereof administered at a flow rate of about 4 mL / min in an injection volume of about 40 mL, and hyaluronidase at a dose of about 500 U / mL.

[0284]

[0294] In some embodiments, the disclosure provides a method for treating a subject at risk for Alzheimer's disease, the method comprising subcutaneously administering to the subject a composition comprising about 6800 mg of an anti-amyloid beta antibody or antigen-binding fragment thereof administered at a flow rate of about 4 mL / min in an injection volume of about 40 mL, and recombinant human hyaluronidase at a dose of about 500 U / mL.

[0285]

[0295] In some embodiments, the present disclosure provides a method for reducing cognitive impairment in a subject, the method comprising subcutaneously administering to the subject a first dose and a second dose, where (a) the first dose comprises about 1700 mg of an anti-amyloid beta antibody or antigen-binding fragment thereof and is administered in an injection volume of 10 mL at a flow rate of about 2 mL / min; (b) the second dose comprises about 3400 mg of an anti-amyloid beta antibody or antigen-binding fragment thereof and is administered in an injection volume of 20 mL at a flow rate of about 2 mL / min. In some embodiments, the first dose is administered on day 1 and the second dose is administered on day 15.

[0286]

[0296] In some embodiments, the disclosure provides a method for reducing cognitive impairment in a subject, the method comprising subcutaneously administering to the subject a first dose and a second dose; (a) a first dose comprises about 3400 mg of an anti-amyloid beta antibody or antigen-binding fragment thereof and is administered in an injection volume of 20 mL at a flow rate of about 4 mL / min; said first dose is co-administered with a permeation enhancer at a dose of about 2000 U / mL; (b) a second dose comprising about 6800 mg of an anti-amyloid beta antibody or antigen-binding fragment thereof administered in an injection volume of 40 mL at a flow rate of about 4 mL / min; said second dose is co-administered with a permeation enhancer at a dose of about 1000 U / mL. In some embodiments, the first dose and the permeation enhancer (at a dose of about 2000 U / mL) are administered on day 1, and the second dose and the permeation enhancer (at a dose of about 1000 U / mL) are administered on day 15.

[0287]

[0297] In some embodiments, the disclosure provides a method for reducing cognitive impairment in a subject, the method comprising subcutaneously administering to the subject a first dose and a second dose; (a) a first dose comprises about 3400 mg of an anti-amyloid beta antibody or antigen-binding fragment thereof and is administered in an injection volume of 20 mL at a flow rate of about 4 mL / min; said first dose is co-administered with hyaluronidase at a dose of about 2000 U / mL; (b) a second dose comprising about 6800 mg of an anti-amyloid beta antibody or antigen-binding fragment thereof administered in an infusion volume of 40 mL at a flow rate of about 4 mL / min; said second dose is co-administered with hyaluronidase at a dose of about 1000 U / mL. In some embodiments, the first dose and hyaluronidase (at a dose of about 2000 U / mL) are administered on day 1 and the second dose and hyaluronidase (at a dose of about 1000 U / mL) are administered on day 15.

[0288]

[0298] In some embodiments, the disclosure provides a method for reducing cognitive impairment in a subject, the method comprising subcutaneously administering to the subject a first dose and a second dose; (a) a first dose comprises about 3400 mg of an anti-amyloid beta antibody or antigen-binding fragment thereof, administered in an injection volume of 20 mL at a flow rate of about 4 mL / min; said first dose is co-administered with recombinant human hyaluronidase at a dose of about 2000 U / mL; (b) a second dose comprising about 6800 mg of an anti-amyloid beta antibody or antigen-binding fragment thereof administered in an infusion volume of 40 mL at a flow rate of about 4 mL / min; said second dose is co-administered with recombinant human hyaluronidase at a dose of about 1000 U / mL. In some embodiments, the first dose and recombinant human hyaluronidase (at a dose of about 2000 U / mL) are administered on day 1 and the second dose and recombinant human hyaluronidase (at a dose of about 1000 U / mL) are administered on day 15.

[0289]

[0299] In some embodiments, the disclosure provides a method for reducing cognitive impairment in a subject, the method comprising subcutaneously administering to the subject a first dose and a second dose, where (a) the first dose comprises about 1700 mg of an anti-amyloid beta antibody or antigen-binding fragment thereof and is administered in an injection volume of 10 mL at a flow rate of about 4 mL / min; (b) the second dose comprises about 3400 mg of an anti-amyloid beta antibody or antigen-binding fragment thereof and is administered in an injection volume of 40 mL at a flow rate of about 4 mL / min. In some embodiments, the first dose is administered on day 1 and the second dose is administered on day 15.

[0290]

[0300] In some embodiments, the disclosure provides a method for reducing cognitive impairment in a subject, the method comprising subcutaneously administering to the subject a first dose and a second dose; (a) the first dose comprises about 3400 mg of an anti-amyloid beta antibody or antigen-binding fragment thereof and is administered in an injection volume of 20 mL at a flow rate of about 4 mL / min; (b) a second dose comprising about 6800 mg of an anti-amyloid beta antibody or antigen-binding fragment thereof administered in an infusion volume of 40 mL at a flow rate of about 4 mL / min; said second dose is co-administered with a permeation enhancer at a dose of about 500 U / mL. In some embodiments, the first dose is administered on day 1 and the second dose and the permeation enhancer are administered on day 15.

[0291]

[0301] In some embodiments, the disclosure provides a method for reducing cognitive impairment in a subject, the method comprising subcutaneously administering to the subject a first dose and a second dose; (a) the first dose comprises about 3400 mg of an anti-amyloid beta antibody or antigen-binding fragment thereof and is administered in an injection volume of 20 mL at a flow rate of about 4 mL / min; (b) a second dose comprising about 6800 mg of an anti-amyloid beta antibody or antigen-binding fragment thereof administered in an infusion volume of 40 mL at a flow rate of about 4 mL / min; said second dose is co-administered with hyaluronidase at a dose of about 500 U / mL. In some embodiments, the first dose is administered on day 1 and the second dose and hyaluronidase are administered on day 15.

[0292]

[0302] In some embodiments, the disclosure provides a method for reducing cognitive impairment in a subject, the method comprising subcutaneously administering to the subject a first dose and a second dose; (a) the first dose comprises about 3400 mg of an anti-amyloid beta antibody or antigen-binding fragment thereof and is administered in an injection volume of 20 mL at a flow rate of about 4 mL / min; (b) a second dose comprising about 6800 mg of an anti-amyloid beta antibody or antigen-binding fragment thereof administered in an infusion volume of 40 mL at a flow rate of about 4 mL / min; said second dose is co-administered with recombinant human hyaluronidase at a dose of about 500 U / mL. In some embodiments, the first dose is administered on day 1 and the second dose and recombinant human hyaluronidase are administered on day 15.

[0293]

[0303] In some embodiments, the disclosure provides a method for reducing cognitive impairment in a subject, the method comprising subcutaneously administering to the subject a first dose and a second dose; (a) a first dose comprises about 3400 mg of an anti-amyloid beta antibody or antigen-binding fragment thereof and is administered in an injection volume of 20 mL at a flow rate of about 4 mL / min; said first dose is co-administered with a permeation enhancer at a dose of about 2000 U / mL; (b) a second dose comprising about 6800 mg of an anti-amyloid beta antibody or antigen-binding fragment thereof administered in an infusion volume of 40 mL at a flow rate of about 4 mL / min; said second dose is co-administered with a permeation enhancer at a dose of about 500 U / mL. In some embodiments, the first dose and the permeation enhancer (at a dose of about 2000 U / mL) are administered on day 1, and the second dose and the permeation enhancer (at a dose of about 500 U / mL) are administered on day 15.

[0294]

[0304] In some embodiments, the disclosure provides a method for reducing cognitive impairment in a subject, the method comprising subcutaneously administering to the subject a first dose and a second dose; (a) a first dose comprises about 3400 mg of an anti-amyloid beta antibody or antigen-binding fragment thereof and is administered in an injection volume of 20 mL at a flow rate of about 4 mL / min; said first dose is co-administered with hyaluronidase at a dose of about 2000 U / mL; (b) a second dose comprising about 6800 mg of an anti-amyloid beta antibody or antigen-binding fragment thereof administered in an infusion volume of 40 mL at a flow rate of about 4 mL / min; said second dose is co-administered with hyaluronidase at a dose of about 500 U / mL. In some embodiments, the first dose and hyaluronidase (at a dose of about 2000 U / mL) are administered on day 1 and the second dose and hyaluronidase (at a dose of about 500 U / mL) are administered on day 15.

[0295]

[0305] In some embodiments, the disclosure provides a method for reducing cognitive impairment in a subject, the method comprising subcutaneously administering to the subject a first dose and a second dose; (a) a first dose comprises about 3400 mg of an anti-amyloid beta antibody or antigen-binding fragment thereof, administered in an injection volume of 20 mL at a flow rate of about 4 mL / min; said first dose is co-administered with recombinant human hyaluronidase at a dose of about 2000 U / mL; (b) a second dose comprising about 6800 mg of an anti-amyloid beta antibody or antigen-binding fragment thereof administered in an infusion volume of 40 mL at a flow rate of about 4 mL / min; said second dose is co-administered with recombinant human hyaluronidase at a dose of about 500 U / mL. In some embodiments, the first dose and recombinant human hyaluronidase (at a dose of about 2000 U / mL) are administered on day 1 and the second dose and recombinant human hyaluronidase (at a dose of about 500 U / mL) are administered on day 15.

[0296]

[0306] In some embodiments, the disclosure provides a method for reducing cognitive impairment in a subject, the method comprising subcutaneously administering to the subject a composition comprising about 6800 mg of an anti-amyloid beta antibody or antigen-binding fragment thereof administered at a flow rate of about 4 mL / min in an injection volume of about 40 mL, and a permeation enhancer at a dose of about 500 U / mL.

[0297]

[0307] In some embodiments, the disclosure provides a method for reducing cognitive impairment in a subject, the method comprising subcutaneously administering to the subject a composition comprising about 6800 mg of an anti-amyloid beta antibody or antigen-binding fragment thereof administered at a flow rate of about 4 mL / min in an injection volume of about 40 mL, and hyaluronidase at a dose of about 500 U / mL.

[0298]

[0308] In some embodiments, the disclosure provides a method for reducing cognitive impairment in a subject, the method comprising subcutaneously administering to the subject a composition comprising about 6800 mg of an anti-amyloid beta antibody or antigen-binding fragment thereof administered at a flow rate of about 4 mL / min in an injection volume of about 40 mL, and recombinant human hyaluronidase at a dose of about 500 U / mL.

[0299]

[0309] In some embodiments, the disclosure provides a method of slowing the progression of cognitive impairment in a subject, the method comprising subcutaneously administering to the subject a first dose and a second dose, where (a) the first dose comprises about 1700 mg of an anti-amyloid beta antibody or antigen-binding fragment thereof and is administered in an injection volume of 10 mL at a flow rate of about 2 mL / min; (b) the second dose comprises about 3400 mg of an anti-amyloid beta antibody or antigen-binding fragment thereof and is administered in an injection volume of 20 mL at a flow rate of about 2 mL / min. In some embodiments, the first dose is administered on day 1 and the second dose is administered on day 15.

[0300]

[0310] In some embodiments, the disclosure provides a method of delaying progression of cognitive impairment in a subject, the method comprising subcutaneously administering to the subject a first dose and a second dose; (a) a first dose comprises about 3400 mg of an anti-amyloid beta antibody or antigen-binding fragment thereof and is administered in an injection volume of 20 mL at a flow rate of about 4 mL / min; said first dose is co-administered with a permeation enhancer at a dose of about 2000 U / mL; (b) a second dose comprising about 6800 mg of an anti-amyloid beta antibody or antigen-binding fragment thereof administered in an injection volume of 40 mL at a flow rate of about 4 mL / min; said second dose is co-administered with a permeation enhancer at a dose of about 1000 U / mL. In some embodiments, the first dose and the permeation enhancer (at a dose of about 2000 U / mL) are administered on day 1, and the second dose and the permeation enhancer (at a dose of about 1000 U / mL) are administered on day 15.

[0301]

[0311] In some embodiments, the disclosure provides a method of delaying progression of cognitive impairment in a subject, the method comprising subcutaneously administering to the subject a first dose and a second dose; (a) a first dose comprises about 3400 mg of an anti-amyloid beta antibody or antigen-binding fragment thereof and is administered in an injection volume of 20 mL at a flow rate of about 4 mL / min; said first dose is co-administered with hyaluronidase at a dose of about 2000 U / mL; (b) a second dose comprising about 6800 mg of an anti-amyloid beta antibody or antigen-binding fragment thereof administered in an infusion volume of 40 mL at a flow rate of about 4 mL / min; said second dose is co-administered with hyaluronidase at a dose of about 1000 U / mL. In some embodiments, the first dose and hyaluronidase (at a dose of about 2000 U / mL) are administered on day 1 and the second dose and hyaluronidase (at a dose of about 1000 U / mL) are administered on day 15.

[0302]

[0312] In some embodiments, the disclosure provides a method of delaying progression of cognitive impairment in a subject, the method comprising subcutaneously administering to the subject a first dose and a second dose; (a) a first dose comprises about 3400 mg of an anti-amyloid beta antibody or antigen-binding fragment thereof, administered in an injection volume of 20 mL at a flow rate of about 4 mL / min; said first dose is co-administered with recombinant human hyaluronidase at a dose of about 2000 U / mL; (b) a second dose comprising about 6800 mg of an anti-amyloid beta antibody or antigen-binding fragment thereof administered in an infusion volume of 40 mL at a flow rate of about 4 mL / min; said second dose is co-administered with recombinant human hyaluronidase at a dose of about 1000 U / mL. In some embodiments, the first dose and recombinant human hyaluronidase (at a dose of about 2000 U / mL) are administered on day 1 and the second dose and recombinant human hyaluronidase (at a dose of about 1000 U / mL) are administered on day 15.

[0303]

[0313] In some embodiments, the disclosure provides a method of slowing the progression of cognitive impairment in a subject, the method comprising subcutaneously administering to the subject a first dose and a second dose, where (a) the first dose comprises about 1700 mg of an anti-amyloid beta antibody or antigen-binding fragment thereof and is administered in an injection volume of 10 mL at a flow rate of about 4 mL / min; (b) the second dose comprises about 3400 mg of an anti-amyloid beta antibody or antigen-binding fragment thereof and is administered in an injection volume of 40 mL at a flow rate of about 4 mL / min. In some embodiments, the first dose is administered on day 1 and the second dose is administered on day 15.

[0304]

[0314] In some embodiments, the disclosure provides a method of delaying progression of cognitive impairment in a subject, the method comprising subcutaneously administering to the subject a first dose and a second dose; (a) the first dose comprises about 3400 mg of an anti-amyloid beta antibody or antigen-binding fragment thereof and is administered in an injection volume of 20 mL at a flow rate of about 4 mL / min; (b) a second dose comprising about 6800 mg of an anti-amyloid beta antibody or antigen-binding fragment thereof administered in an infusion volume of 40 mL at a flow rate of about 4 mL / min; said second dose is co-administered with a permeation enhancer at a dose of about 500 U / mL. In some embodiments, the first dose is administered on day 1 and the second dose and the permeation enhancer are administered on day 15.

[0305]

[0315] In some embodiments, the disclosure provides a method of delaying progression of cognitive impairment in a subject, the method comprising subcutaneously administering to the subject a first dose and a second dose; (a) the first dose comprises about 3400 mg of an anti-amyloid beta antibody or antigen-binding fragment thereof and is administered in an injection volume of 20 mL at a flow rate of about 4 mL / min; (b) a second dose comprising about 6800 mg of an anti-amyloid beta antibody or antigen-binding fragment thereof administered in an infusion volume of 40 mL at a flow rate of about 4 mL / min; said second dose is co-administered with hyaluronidase at a dose of about 500 U / mL. In some embodiments, the first dose is administered on day 1 and the second dose and hyaluronidase are administered on day 15.

[0306]

[0316] In some embodiments, the disclosure provides a method of delaying progression of cognitive impairment in a subject, the method comprising subcutaneously administering to the subject a first dose and a second dose; (a) the first dose comprises about 3400 mg of an anti-amyloid beta antibody or antigen-binding fragment thereof and is administered in an injection volume of 20 mL at a flow rate of about 4 mL / min; (b) a second dose comprising about 6800 mg of an anti-amyloid beta antibody or antigen-binding fragment thereof administered in an infusion volume of 40 mL at a flow rate of about 4 mL / min; said second dose is co-administered with recombinant human hyaluronidase at a dose of about 500 U / mL. In some embodiments, the first dose is administered on day 1 and the second dose and recombinant human hyaluronidase are administered on day 15.

[0307]

[0317] In some embodiments, the disclosure provides a method of delaying progression of cognitive impairment in a subject, the method comprising subcutaneously administering to the subject a first dose and a second dose; (a) a first dose comprises about 3400 mg of an anti-amyloid beta antibody or antigen-binding fragment thereof and is administered in an injection volume of 20 mL at a flow rate of about 4 mL / min; said first dose is co-administered with a permeation enhancer at a dose of about 2000 U / mL; (b) a second dose comprising about 6800 mg of an anti-amyloid beta antibody or antigen-binding fragment thereof administered in an infusion volume of 40 mL at a flow rate of about 4 mL / min; said second dose is co-administered with a permeation enhancer at a dose of about 500 U / mL. In some embodiments, the first dose and the permeation enhancer (at a dose of about 2000 U / mL) are administered on day 1, and the second dose and the permeation enhancer (at a dose of about 500 U / mL) are administered on day 15.

[0308]

[0318] In some embodiments, the disclosure provides a method of delaying progression of cognitive impairment in a subject, the method comprising subcutaneously administering to the subject a first dose and a second dose; (a) a first dose comprises about 3400 mg of an anti-amyloid beta antibody or antigen-binding fragment thereof and is administered in an injection volume of 20 mL at a flow rate of about 4 mL / min; said first dose is co-administered with hyaluronidase at a dose of about 2000 U / mL; (b) a second dose comprising about 6800 mg of an anti-amyloid beta antibody or antigen-binding fragment thereof administered in an infusion volume of 40 mL at a flow rate of about 4 mL / min; said second dose is co-administered with hyaluronidase at a dose of about 500 U / mL. In some embodiments, the first dose and hyaluronidase (at a dose of about 2000 U / mL) are administered on day 1 and the second dose and hyaluronidase (at a dose of about 500 U / mL) are administered on day 15.

[0309]

[0319] In some embodiments, the disclosure provides a method of delaying progression of cognitive impairment in a subject, the method comprising subcutaneously administering to the subject a first dose and a second dose; (a) a first dose comprises about 3400 mg of an anti-amyloid beta antibody or antigen-binding fragment thereof, administered in an injection volume of 20 mL at a flow rate of about 4 mL / min; said first dose is co-administered with recombinant human hyaluronidase at a dose of about 2000 U / mL; (b) a second dose comprising about 6800 mg of an anti-amyloid beta antibody or antigen-binding fragment thereof administered in an infusion volume of 40 mL at a flow rate of about 4 mL / min; said second dose is co-administered with recombinant human hyaluronidase at a dose of about 500 U / mL. In some embodiments, the first dose and recombinant human hyaluronidase (at a dose of about 2000 U / mL) are administered on day 1 and the second dose and recombinant human hyaluronidase (at a dose of about 500 U / mL) are administered on day 15.

[0310]

[0320] In some embodiments, the disclosure provides a method of slowing the progression of cognitive impairment in a subject, the method comprising subcutaneously administering to the subject a composition comprising about 6800 mg of an anti-amyloid beta antibody or antigen-binding fragment thereof administered at a flow rate of about 4 mL / min in an injection volume of about 40 mL, and a permeation enhancer at a dose of about 500 U / mL.

[0311]

[0321] In some embodiments, the disclosure provides a method of slowing the progression of cognitive impairment in a subject, the method comprising subcutaneously administering to the subject a composition comprising about 6800 mg of an anti-amyloid beta antibody or antigen-binding fragment thereof administered at a flow rate of about 4 mL / min in an injection volume of about 40 mL, and hyaluronidase at a dose of about 500 U / mL.

[0312]

[0322] In some embodiments, the disclosure provides a method of slowing the progression of cognitive impairment in a subject, the method comprising subcutaneously administering to the subject a composition comprising about 6800 mg of an anti-amyloid beta antibody or antigen-binding fragment thereof administered at a flow rate of about 4 mL / min in an injection volume of about 40 mL, and recombinant human hyaluronidase at a dose of about 500 U / mL.

[0313]

[0323] In some embodiments, the disclosure provides a method of slowing progression in a subject diagnosed with early or mild-to-moderate Alzheimer's disease (AD), the method comprising subcutaneously administering to the subject a first dose and a second dose, where (a) the first dose comprises about 1700 mg of an anti-amyloid beta antibody or antigen-binding fragment thereof and is administered in an injection volume of 10 mL at a flow rate of about 2 mL / min; (b) the second dose comprises about 3400 mg of an anti-amyloid beta antibody or antigen-binding fragment thereof and is administered in an injection volume of 20 mL at a flow rate of about 2 mL / min. In some embodiments, the first dose is administered on day 1 and the second dose is administered on day 15.

[0314]

[0324] In some embodiments, the disclosure provides a method for delaying progression in a subject diagnosed with early or mild-to-moderate Alzheimer's disease (AD), the method comprising subcutaneously administering to the subject a first dose and a second dose; (a) a first dose comprises about 3400 mg of an anti-amyloid beta antibody or antigen-binding fragment thereof and is administered in an injection volume of 20 mL at a flow rate of about 4 mL / min; said first dose is co-administered with a permeation enhancer at a dose of about 2000 U / mL; (b) a second dose comprising about 6800 mg of an anti-amyloid beta antibody or antigen-binding fragment thereof administered in an injection volume of 40 mL at a flow rate of about 4 mL / min; said second dose is co-administered with a permeation enhancer at a dose of about 1000 U / mL. In some embodiments, the first dose and recombinant human hyaluronidase (at a dose of about 2000 U / mL) are administered on day 1 and the second dose and recombinant human hyaluronidase (at a dose of about 1000 U / mL) are administered on day 15.

[0315]

[0325] In some embodiments, the disclosure provides a method for delaying progression in a subject diagnosed with early or mild-to-moderate Alzheimer's disease (AD), the method comprising subcutaneously administering to the subject a first dose and a second dose; (a) a first dose comprises about 3400 mg of an anti-amyloid beta antibody or antigen-binding fragment thereof and is administered in an injection volume of 20 mL at a flow rate of about 4 mL / min; said first dose is co-administered with hyaluronidase at a dose of about 2000 U / mL; (b) a second dose comprising about 6800 mg of an anti-amyloid beta antibody or antigen-binding fragment thereof administered in an infusion volume of 40 mL at a flow rate of about 4 mL / min; said second dose is co-administered with hyaluronidase at a dose of about 1000 U / mL. In some embodiments, the first dose and hyaluronidase (at a dose of about 2000 U / mL) are administered on day 1 and the second dose and hyaluronidase (at a dose of about 1000 U / mL) are administered on day 15.

[0316]

[0326] In some embodiments, the disclosure provides a method for delaying progression in a subject diagnosed with early or mild-to-moderate Alzheimer's disease (AD), the method comprising subcutaneously administering to the subject a first dose and a second dose; (a) a first dose comprises about 3400 mg of an anti-amyloid beta antibody or antigen-binding fragment thereof, administered in an injection volume of 20 mL at a flow rate of about 4 mL / min; said first dose is co-administered with recombinant human hyaluronidase at a dose of about 2000 U / mL; (b) a second dose comprising about 6800 mg of an anti-amyloid beta antibody or antigen-binding fragment thereof administered in an infusion volume of 40 mL at a flow rate of about 4 mL / min; said second dose is co-administered with recombinant human hyaluronidase at a dose of about 1000 U / mL. In some embodiments, the first dose and recombinant human hyaluronidase (at a dose of about 2000 U / mL) are administered on day 1 and the second dose and recombinant human hyaluronidase (at a dose of about 1000 U / mL) are administered on day 15.

[0317]

[0327] In some embodiments, the disclosure provides a method of slowing progression in a subject diagnosed with early or mild-to-moderate Alzheimer's disease (AD), the method comprising subcutaneously administering to the subject a first dose and a second dose, where (a) the first dose comprises about 1700 mg of an anti-amyloid beta antibody or antigen-binding fragment thereof and is administered in an injection volume of 10 mL at a flow rate of about 4 mL / min; (b) the second dose comprises about 3400 mg of an anti-amyloid beta antibody or antigen-binding fragment thereof and is administered in an injection volume of 40 mL at a flow rate of about 4 mL / min. In some embodiments, the first dose is administered on day 1 and the second dose is administered on day 15.

[0318]

[0328] In some embodiments, the disclosure provides a method of slowing progression in a subject diagnosed with early or mild-to-moderate Alzheimer's disease (AD), the method comprising subcutaneously administering to the subject a first dose and a second dose; (a) the first dose comprises about 3400 mg of an anti-amyloid beta antibody or antigen-binding fragment thereof and is administered in an injection volume of 20 mL at a flow rate of about 4 mL / min; (b) a second dose comprising about 6800 mg of an anti-amyloid beta antibody or antigen-binding fragment thereof administered in an infusion volume of 40 mL at a flow rate of about 4 mL / min; said second dose is co-administered with a permeation enhancer at a dose of about 500 U / mL. In some embodiments, the first dose is administered on day 1 and the second dose and the permeation enhancer are administered on day 15.

[0319]

[0329] In some embodiments, the disclosure provides a method of slowing progression in a subject diagnosed with early or mild-to-moderate Alzheimer's disease (AD), the method comprising subcutaneously administering to the subject a first dose and a second dose; (a) the first dose comprises about 3400 mg of an anti-amyloid beta antibody or antigen-binding fragment thereof and is administered in an injection volume of 20 mL at a flow rate of about 4 mL / min; (b) a second dose comprising about 6800 mg of an anti-amyloid beta antibody or antigen-binding fragment thereof administered in an infusion volume of 40 mL at a flow rate of about 4 mL / min; said second dose is co-administered with hyaluronidase at a dose of about 500 U / mL. In some embodiments, the first dose is administered on day 1 and the second dose and hyaluronidase are administered on day 15.

[0320]

[0330] In some embodiments, the disclosure provides a method of slowing progression in a subject diagnosed with early or mild-to-moderate Alzheimer's disease (AD), the method comprising subcutaneously administering to the subject a first dose and a second dose; (a) the first dose comprises about 3400 mg of an anti-amyloid beta antibody or antigen-binding fragment thereof and is administered in an injection volume of 20 mL at a flow rate of about 4 mL / min; (b) a second dose comprising about 6800 mg of an anti-amyloid beta antibody or antigen-binding fragment thereof administered in an infusion volume of 40 mL at a flow rate of about 4 mL / min; said second dose is co-administered with recombinant human hyaluronidase at a dose of about 500 U / mL. In some embodiments, the first dose is administered on day 1 and the second dose and recombinant human hyaluronidase are administered on day 15.

[0321]

[0331] In some embodiments, the disclosure provides a method for delaying progression in a subject diagnosed with early or mild-to-moderate Alzheimer's disease (AD), the method comprising subcutaneously administering to the subject a first dose and a second dose; (a) a first dose comprises about 3400 mg of an anti-amyloid beta antibody or antigen-binding fragment thereof and is administered in an injection volume of 20 mL at a flow rate of about 4 mL / min; said first dose is co-administered with a permeation enhancer at a dose of about 2000 U / mL; (b) a second dose comprising about 6800 mg of an anti-amyloid beta antibody or antigen-binding fragment thereof administered in an infusion volume of 40 mL at a flow rate of about 4 mL / min; said second dose is co-administered with a permeation enhancer at a dose of about 500 U / mL. In some embodiments, the first dose and the permeation enhancer (at a dose of about 2000 U / mL) are administered on day 1, and the second dose and the permeation enhancer (at a dose of about 500 U / mL) are administered on day 15.

[0322]

[0332] In some embodiments, the disclosure provides a method for delaying progression in a subject diagnosed with early or mild-to-moderate Alzheimer's disease (AD), the method comprising subcutaneously administering to the subject a first dose and a second dose; (a) a first dose comprises about 3400 mg of an anti-amyloid beta antibody or antigen-binding fragment thereof and is administered in an injection volume of 20 mL at a flow rate of about 4 mL / min; said first dose is co-administered with hyaluronidase at a dose of about 2000 U / mL; (b) a second dose comprising about 6800 mg of an anti-amyloid beta antibody or antigen-binding fragment thereof administered in an infusion volume of 40 mL at a flow rate of about 4 mL / min; said second dose is co-administered with hyaluronidase at a dose of about 500 U / mL. In some embodiments, the first dose and hyaluronidase (at a dose of about 2000 U / mL) are administered on day 1 and the second dose and hyaluronidase (at a dose of about 500 U / mL) are administered on day 15.

[0323]

[0333] In some embodiments, the disclosure provides a method for delaying progression in a subject diagnosed with early or mild-to-moderate Alzheimer's disease (AD), the method comprising subcutaneously administering to the subject a first dose and a second dose; (a) a first dose comprises about 3400 mg of an anti-amyloid beta antibody or antigen-binding fragment thereof, administered in an injection volume of 20 mL at a flow rate of about 4 mL / min; said first dose is co-administered with recombinant human hyaluronidase at a dose of about 2000 U / mL; (b) a second dose comprising about 6800 mg of an anti-amyloid beta antibody or antigen-binding fragment thereof administered in an infusion volume of 40 mL at a flow rate of about 4 mL / min; said second dose is co-administered with recombinant human hyaluronidase at a dose of about 500 U / mL. In some embodiments, the first dose and recombinant human hyaluronidase (at a dose of about 2000 U / mL) are administered on day 1 and the second dose and recombinant human hyaluronidase (at a dose of about 500 U / mL) are administered on day 15.

[0324]

[0334] In some embodiments, the disclosure provides a method of slowing progression in a subject diagnosed with early or mild-to-moderate Alzheimer's disease (AD), the method comprising subcutaneously administering to the subject a composition comprising about 6800 mg of an anti-amyloid beta antibody or antigen-binding fragment thereof administered at a flow rate of about 4 mL / min in an injection volume of about 40 mL, and a permeation enhancer at a dose of about 500 U / mL.

[0325]

[0335] In some embodiments, the disclosure provides a method of slowing progression in a subject diagnosed with early or mild-to-moderate Alzheimer's disease (AD), the method comprising subcutaneously administering to the subject a composition comprising about 6800 mg of an anti-amyloid beta antibody or antigen-binding fragment thereof administered at a flow rate of about 4 mL / min in an injection volume of about 40 mL, and hyaluronidase at a dose of about 500 U / mL.

[0326]

[0336] In some embodiments, the disclosure provides a method of slowing progression in a subject diagnosed with early or mild-to-moderate Alzheimer's disease (AD), the method comprising subcutaneously administering to the subject a composition comprising about 6800 mg of an anti-amyloid beta antibody or antigen-binding fragment thereof administered at a flow rate of about 4 mL / min in an injection volume of about 40 mL, and recombinant human hyaluronidase at a dose of about 500 U / mL.

[0327]

[0337] In some embodiments, the disclosure provides a method of treating early or mild-to-moderate AD without increasing the risk of adverse events, the method comprising subcutaneously administering to a subject a first dose and a second dose, where (a) the first dose comprises about 1700 mg of an anti-amyloid beta antibody or antigen-binding fragment thereof and is administered in an injection volume of 10 mL at a flow rate of about 2 mL / min; (b) the second dose comprises about 3400 mg of an anti-amyloid beta antibody or antigen-binding fragment thereof and is administered in an injection volume of 20 mL at a flow rate of about 2 mL / min. In some embodiments, the first dose is administered on day 1 and the second dose is administered on day 15.

[0328]

[0338] In some embodiments, the disclosure provides a method of treating early or mild-to-moderate AD without increasing the risk of adverse events, the method comprising subcutaneously administering to a subject a first dose and a second dose; (a) a first dose comprises about 3400 mg of an anti-amyloid beta antibody or antigen-binding fragment thereof and is administered in an injection volume of 20 mL at a flow rate of about 4 mL / min; said first dose is co-administered with a permeation enhancer at a dose of about 2000 U / mL; (b) a second dose comprising about 6800 mg of an anti-amyloid beta antibody or antigen-binding fragment thereof administered in an injection volume of 40 mL at a flow rate of about 4 mL / min; said second dose is co-administered with a permeation enhancer at a dose of about 1000 U / mL. In some embodiments, the first dose and the permeation enhancer (at a dose of about 2000 U / mL) are administered on day 1, and the second dose and the permeation enhancer (at a dose of about 1000 U / mL) are administered on day 15.

[0329]

[0339] In some embodiments, the disclosure provides a method of treating early or mild-to-moderate AD without increasing the risk of adverse events, the method comprising subcutaneously administering to a subject a first dose and a second dose; (a) a first dose comprises about 3400 mg of an anti-amyloid beta antibody or antigen-binding fragment thereof and is administered in an injection volume of 20 mL at a flow rate of about 4 mL / min; said first dose is co-administered with hyaluronidase at a dose of about 2000 U / mL; (b) a second dose comprising about 6800 mg of an anti-amyloid beta antibody or antigen-binding fragment thereof administered in an infusion volume of 40 mL at a flow rate of about 4 mL / min; said second dose is co-administered with hyaluronidase at a dose of about 1000 U / mL. In some embodiments, the first dose and hyaluronidase (at a dose of about 2000 U / mL) are administered on day 1 and the second dose and hyaluronidase (at a dose of about 1000 U / mL) are administered on day 15.

[0330]

[0340] In some embodiments, the disclosure provides a method of treating early or mild-to-moderate AD without increasing the risk of adverse events, the method comprising subcutaneously administering to a subject a first dose and a second dose; (a) a first dose comprises about 3400 mg of an anti-amyloid beta antibody or antigen-binding fragment thereof, administered in an injection volume of 20 mL at a flow rate of about 4 mL / min; said first dose is co-administered with recombinant human hyaluronidase at a dose of about 2000 U / mL; (b) a second dose comprising about 6800 mg of an anti-amyloid beta antibody or antigen-binding fragment thereof administered in an infusion volume of 40 mL at a flow rate of about 4 mL / min; said second dose is co-administered with recombinant human hyaluronidase at a dose of about 1000 U / mL. In some embodiments, the first dose and recombinant human hyaluronidase (at a dose of about 2000 U / mL) are administered on day 1 and the second dose and recombinant human hyaluronidase (at a dose of about 1000 U / mL) are administered on day 15.

[0331]

[0341] In some embodiments, the disclosure provides a method of treating early or mild-to-moderate AD without increasing the risk of adverse events, the method comprising subcutaneously administering to a subject a first dose and a second dose, where (a) the first dose comprises about 1700 mg of an anti-amyloid beta antibody or antigen-binding fragment thereof and is administered in an injection volume of 10 mL at a flow rate of about 4 vmL / min; (b) the second dose comprises about 3400 mg of an anti-amyloid beta antibody or antigen-binding fragment thereof and is administered in an injection volume of 40 mL at a flow rate of about 4 mL / min. In some embodiments, the first dose is administered on day 1 and the second dose is administered on day 15.

[0332]

[0342] In some embodiments, the disclosure provides a method of treating mild to moderate AD without increasing the risk of adverse events, the method comprising subcutaneously administering to a subject a first dose and a second dose; (a) the first dose comprises about 3400 mg of an anti-amyloid beta antibody or antigen-binding fragment thereof and is administered in an injection volume of 20 mL at a flow rate of about 4 mL / min; (b) a second dose comprising about 6800 mg of an anti-amyloid beta antibody or antigen-binding fragment thereof administered in an infusion volume of 40 mL at a flow rate of about 4 mL / min; said second dose is co-administered with a permeation enhancer at a dose of about 500 U / mL. In some embodiments, the first dose is administered on day 1 and the second dose and the permeation enhancer are administered on day 15.

[0333]

[0343] In some embodiments, the disclosure provides a method of treating mild to moderate AD without increasing the risk of adverse events, the method comprising subcutaneously administering to a subject a first dose and a second dose; (a) the first dose comprises about 3400 mg of an anti-amyloid beta antibody or antigen-binding fragment thereof and is administered in an injection volume of 20 mL at a flow rate of about 4 mL / min; (b) a second dose comprising about 6800 mg of an anti-amyloid beta antibody or antigen-binding fragment thereof administered in an infusion volume of 40 mL at a flow rate of about 4 mL / min; said second dose is co-administered with hyaluronidase at a dose of about 500 U / mL. In some embodiments, the first dose is administered on day 1 and the second dose and hyaluronidase are administered on day 15.

[0334]

[0344] In some embodiments, the disclosure provides a method of treating mild to moderate AD without increasing the risk of adverse events, the method comprising subcutaneously administering to a subject a first dose and a second dose; (a) the first dose comprises about 3400 mg of an anti-amyloid beta antibody or antigen-binding fragment thereof and is administered in an injection volume of 20 mL at a flow rate of about 4 mL / min; (b) a second dose comprising about 6800 mg of an anti-amyloid beta antibody or antigen-binding fragment thereof administered in an infusion volume of 40 mL at a flow rate of about 4 mL / min; said second dose is co-administered with recombinant human hyaluronidase at a dose of about 500 U / mL. In some embodiments, the first dose is administered on day 1 and the second dose and recombinant human hyaluronidase are administered on day 15.

[0335]

[0345] In some embodiments, the disclosure provides a method of treating early or mild-to-moderate AD without increasing the risk of adverse events, the method comprising subcutaneously administering to a subject a first dose and a second dose; (a) a first dose comprises about 3400 mg of an anti-amyloid beta antibody or antigen-binding fragment thereof and is administered in an injection volume of 20 mL at a flow rate of about 4 mL / min; said first dose is co-administered with a permeation enhancer at a dose of about 2000 U / mL; (b) a second dose comprising about 6800 mg of an anti-amyloid beta antibody or antigen-binding fragment thereof administered in an infusion volume of 40 mL at a flow rate of about 4 mL / min; said second dose is co-administered with a permeation enhancer at a dose of about 500 U / mL. In some embodiments, the first dose and the permeation enhancer (at a dose of about 2000 U / mL) are administered on day 1, and the second dose and the permeation enhancer (at a dose of about 500 U / mL) are administered on day 15.

[0336]

[0346] In some embodiments, the disclosure provides a method of treating early or mild-to-moderate AD without increasing the risk of adverse events, the method comprising subcutaneously administering to a subject a first dose and a second dose; (a) a first dose comprises about 3400 mg of an anti-amyloid beta antibody or antigen-binding fragment thereof and is administered in an injection volume of 20 mL at a flow rate of about 4 mL / min; said first dose is co-administered with hyaluronidase at a dose of about 2000 U / mL; (b) a second dose comprising about 6800 mg of an anti-amyloid beta antibody or antigen-binding fragment thereof administered in an infusion volume of 40 mL at a flow rate of about 4 mL / min; said second dose is co-administered with hyaluronidase at a dose of about 500 U / mL. In some embodiments, the first dose and hyaluronidase (at a dose of about 2000 U / mL) are administered on day 1 and the second dose and hyaluronidase (at a dose of about 500 U / mL) are administered on day 15.

[0337]

[0347] In some embodiments, the disclosure provides a method of treating early or mild-to-moderate AD without increasing the risk of adverse events, the method comprising subcutaneously administering to a subject a first dose and a second dose; (a) a first dose comprises about 3400 mg of an anti-amyloid beta antibody or antigen-binding fragment thereof, administered in an injection volume of 20 mL at a flow rate of about 4 mL / min; said first dose is co-administered with recombinant human hyaluronidase at a dose of about 2000 U / mL; (b) a second dose comprising about 6800 mg of an anti-amyloid beta antibody or antigen-binding fragment thereof administered in an infusion volume of 40 mL at a flow rate of about 4 mL / min; said second dose is co-administered with recombinant human hyaluronidase at a dose of about 500 U / mL. In some embodiments, the first dose and recombinant human hyaluronidase (at a dose of about 2000 U / mL) are administered on day 1 and the second dose and recombinant human hyaluronidase (at a dose of about 500 U / mL) are administered on day 15.

[0338]

[0348] In some embodiments, the disclosure provides a method of treating early or mild-to-moderate AD without increasing the risk of adverse events, the method comprising subcutaneously administering to a subject a composition comprising about 6800 mg of an anti-amyloid beta antibody or antigen-binding fragment thereof administered at a flow rate of about 4 mL / min in an injection volume of about 40 mL, and a permeation enhancer at a dose of about 500 U / mL.

[0339]

[0349] In some embodiments, the disclosure provides a method of treating early or mild-to-moderate AD without increasing the risk of adverse events, the method comprising subcutaneously administering to a subject a composition comprising about 6800 mg of an anti-amyloid beta antibody or antigen-binding fragment thereof administered at a flow rate of about 4 mL / min in an injection volume of about 40 mL, and hyaluronidase at a dose of about 500 U / mL.

[0340]

[0350] In some embodiments, the disclosure provides a method of treating early or mild-to-moderate AD without increasing the risk of adverse events, the method comprising subcutaneously administering to a subject a composition comprising about 6800 mg of an anti-amyloid beta antibody or antigen-binding fragment thereof administered at a flow rate of about 4 mL / min in an injection volume of about 40 mL, and recombinant human hyaluronidase at a dose of about 500 U / mL.

[0341]

[0351] In some embodiments, the disclosure provides a method of delaying clinical deterioration in a patient diagnosed with early or mild-to-moderate Alzheimer's disease (AD), the method comprising subcutaneously administering to the subject a first dose and a second dose, where (a) the first dose comprises about 1700 mg of an anti-amyloid beta antibody or antigen-binding fragment thereof and is administered in an injection volume of 10 mL at a flow rate of about 2 mL / min; and (b) the second dose comprises about 3400 mg of an anti-amyloid beta antibody or antigen-binding fragment thereof and is administered in an injection volume of 20 mL at a flow rate of about 2 mL / min. In some embodiments, the first dose is administered on day 1 and the second dose is administered on day 15.

[0342]

[0352] In some embodiments, the disclosure provides a method of delaying clinical deterioration in a patient diagnosed with early or mild-to-moderate Alzheimer's disease (AD), the method comprising subcutaneously administering to the subject a first dose and a second dose; (a) a first dose comprises about 3400 mg of an anti-amyloid beta antibody or antigen-binding fragment thereof and is administered in an injection volume of 20 mL at a flow rate of about 4 mL / min; said first dose is co-administered with a permeation enhancer at a dose of about 2000 U / mL; (b) a second dose comprising about 6800 mg of an anti-amyloid beta antibody or antigen-binding fragment thereof administered in an injection volume of 40 mL at a flow rate of about 4 mL / min; said second dose is co-administered with a permeation enhancer at a dose of about 1000 U / mL. In some embodiments, the first dose and the permeation enhancer (at a dose of about 2000 U / mL) are administered on day 1, and the second dose and the permeation enhancer (at a dose of about 1000 U / mL) are administered on day 15.

[0343]

[0353] In some embodiments, the disclosure provides a method of delaying clinical deterioration in a patient diagnosed with early or mild-to-moderate Alzheimer's disease (AD), the method comprising subcutaneously administering to the subject a first dose and a second dose; (a) a first dose comprises about 3400 mg of an anti-amyloid beta antibody or antigen-binding fragment thereof and is administered in an injection volume of 20 mL at a flow rate of about 4 mL / min; said first dose is co-administered with hyaluronidase at a dose of about 2000 U / mL; (b) a second dose comprising about 6800 mg of an anti-amyloid beta antibody or antigen-binding fragment thereof administered in an infusion volume of 40 mL at a flow rate of about 4 mL / min; said second dose is co-administered with hyaluronidase at a dose of about 1000 U / mL. In some embodiments, the first dose and hyaluronidase (at a dose of about 2000 U / mL) are administered on day 1 and the second dose and hyaluronidase (at a dose of about 1000 U / mL) are administered on day 15.

[0344]

[0354] In some embodiments, the disclosure provides a method of delaying clinical deterioration in a patient diagnosed with early or mild-to-moderate Alzheimer's disease (AD), the method comprising subcutaneously administering to the subject a first dose and a second dose; (a) a first dose comprises about 3400 mg of an anti-amyloid beta antibody or antigen-binding fragment thereof, administered in an injection volume of 20 mL at a flow rate of about 4 mL / min; said first dose is co-administered with recombinant human hyaluronidase at a dose of about 2000 U / mL; (b) a second dose comprising about 6800 mg of an anti-amyloid beta antibody or antigen-binding fragment thereof administered in an infusion volume of 40 mL at a flow rate of about 4 mL / min; said second dose is co-administered with recombinant human hyaluronidase at a dose of about 1000 U / mL. In some embodiments, the first dose and recombinant human hyaluronidase (at a dose of about 2000 U / mL) are administered on day 1 and the second dose and recombinant human hyaluronidase (at a dose of about 1000 U / mL) are administered on day 15.

[0345]

[0355] In some embodiments, the disclosure provides a method of delaying clinical deterioration in a patient diagnosed with early or mild-to-moderate Alzheimer's disease (AD), the method comprising subcutaneously administering to the subject a first dose and a second dose, where (a) the first dose comprises about 1700 mg of an anti-amyloid beta antibody or antigen-binding fragment thereof and is administered in an injection volume of 10 mL at a flow rate of about 4 mL / min; (b) the second dose comprises about 3400 mg of an anti-amyloid beta antibody or antigen-binding fragment thereof and is administered in an injection volume of 40 mL at a flow rate of about 4 mL / min. In some embodiments, the first dose is administered on day 1 and the second dose is administered on day 15.

[0346]

[0356] In some embodiments, the disclosure provides a method of delaying clinical deterioration in a patient diagnosed with early or mild-to-moderate Alzheimer's disease (AD), the method comprising subcutaneously administering to the subject a first dose and a second dose; (a) the first dose comprises about 3400 mg of an anti-amyloid beta antibody or antigen-binding fragment thereof and is administered in an injection volume of 20 mL at a flow rate of about 4 mL / min; (b) a second dose comprising about 6800 mg of an anti-amyloid beta antibody or antigen-binding fragment thereof administered in an infusion volume of 40 mL at a flow rate of about 4 mL / min; said second dose is co-administered with a permeation enhancer at a dose of about 500 U / mL. In some embodiments, the first dose is administered on day 1 and the second dose and the permeation enhancer are administered on day 15.

[0347]

[0357] In some embodiments, the disclosure provides a method of delaying clinical deterioration in a patient diagnosed with early or mild-to-moderate Alzheimer's disease (AD), the method comprising subcutaneously administering to the subject a first dose and a second dose; (a) the first dose comprises about 3400 mg of an anti-amyloid beta antibody or antigen-binding fragment thereof and is administered in an injection volume of 20 mL at a flow rate of about 4 mL / min; (b) a second dose comprising about 6800 mg of an anti-amyloid beta antibody or antigen-binding fragment thereof administered in an infusion volume of 40 mL at a flow rate of about 4 mL / min; said second dose is co-administered with hyaluronidase at a dose of about 500 U / mL. In some embodiments, the first dose is administered on day 1 and the second dose and hyaluronidase are administered on day 15.

[0348]

[0358] In some embodiments, the disclosure provides a method of delaying clinical deterioration in a patient diagnosed with early or mild-to-moderate Alzheimer's disease (AD), the method comprising subcutaneously administering to the subject a first dose and a second dose; (a) the first dose comprises about 3400 mg of an anti-amyloid beta antibody or antigen-binding fragment thereof and is administered in an injection volume of 20 mL at a flow rate of about 4 mL / min; (b) a second dose comprising about 6800 mg of an anti-amyloid beta antibody or antigen-binding fragment thereof administered in an infusion volume of 40 mL at a flow rate of about 4 mL / min; said second dose is co-administered with recombinant human hyaluronidase at a dose of about 500 U / mL. In some embodiments, the first dose is administered on day 1 and the second dose and recombinant human hyaluronidase are administered on day 15.

[0349]

[0359] In some embodiments, the disclosure provides a method of delaying clinical deterioration in a patient diagnosed with early or mild-to-moderate Alzheimer's disease (AD), the method comprising subcutaneously administering to the subject a first dose and a second dose; (a) a first dose comprises about 3400 mg of an anti-amyloid beta antibody or antigen-binding fragment thereof and is administered in an injection volume of 20 mL at a flow rate of about 4 mL / min; said first dose is co-administered with a permeation enhancer at a dose of about 2000 U / mL; (b) a second dose comprising about 6800 mg of an anti-amyloid beta antibody or antigen-binding fragment thereof administered in an infusion volume of 40 mL at a flow rate of about 4 mL / min; said second dose is co-administered with a permeation enhancer at a dose of about 500 U / mL. In some embodiments, the first dose and the permeation enhancer (at a dose of about 2000 U / mL) are administered on day 1, and the second dose and the permeation enhancer (at a dose of about 500 U / mL) are administered on day 15.

[0350]

[0360] In some embodiments, the disclosure provides a method of delaying clinical deterioration in a patient diagnosed with early or mild-to-moderate Alzheimer's disease (AD), the method comprising subcutaneously administering to the subject a first dose and a second dose; (a) a first dose comprises about 3400 mg of an anti-amyloid beta antibody or antigen-binding fragment thereof and is administered in an injection volume of 20 mL at a flow rate of about 4 mL / min; said first dose is co-administered with hyaluronidase at a dose of about 2000 U / mL; (b) a second dose comprising about 6800 mg of an anti-amyloid beta antibody or antigen-binding fragment thereof administered in an infusion volume of 40 mL at a flow rate of about 4 mL / min; said second dose is co-administered with hyaluronidase at a dose of about 500 U / mL. In some embodiments, the first dose and hyaluronidase (at a dose of about 2000 U / mL) are administered on day 1 and the second dose and hyaluronidase (at a dose of about 500 U / mL) are administered on day 15.

[0351]

[0361] In some embodiments, the disclosure provides a method of delaying clinical deterioration in a patient diagnosed with early or mild-to-moderate Alzheimer's disease (AD), the method comprising subcutaneously administering to the subject a first dose and a second dose; (a) a first dose comprises about 3400 mg of an anti-amyloid beta antibody or antigen-binding fragment thereof, administered in an injection volume of 20 mL at a flow rate of about 4 mL / min; said first dose is co-administered with recombinant human hyaluronidase at a dose of about 2000 U / mL; (b) a second dose comprising about 6800 mg of an anti-amyloid beta antibody or antigen-binding fragment thereof administered in an infusion volume of 40 mL at a flow rate of about 4 mL / min; said second dose is co-administered with recombinant human hyaluronidase at a dose of about 500 U / mL. In some embodiments, the first dose and recombinant human hyaluronidase (at a dose of about 2000 U / mL) are administered on day 1 and the second dose and recombinant human hyaluronidase (at a dose of about 500 U / mL) are administered on day 15.

[0352]

[0362] In some embodiments, the disclosure provides a method of delaying clinical deterioration in a patient diagnosed with early or mild-to-moderate Alzheimer's disease (AD), the method comprising subcutaneously administering to a subject a composition comprising about 6800 mg of an anti-amyloid beta antibody or antigen-binding fragment thereof administered at a flow rate of about 4 mL / min in an injection volume of about 40 mL, and a permeation enhancer at a dose of about 500 U / mL.

[0353]

[0363] In some embodiments, the disclosure provides a method of delaying clinical deterioration in a patient diagnosed with early or mild-to-moderate Alzheimer's disease (AD), the method comprising subcutaneously administering to a subject a composition comprising about 6800 mg of an anti-amyloid beta antibody or antigen-binding fragment thereof administered at a flow rate of about 4 mL / min in an injection volume of about 40 mL, and hyaluronidase at a dose of about 500 U / mL.

[0354]

[0364] In some embodiments, the disclosure provides a method of delaying clinical deterioration in a patient diagnosed with early or mild-to-moderate Alzheimer's disease (AD), the method comprising subcutaneously administering to a subject a composition comprising about 6800 mg of an anti-amyloid beta antibody or antigen-binding fragment thereof administered at a flow rate of about 4 mL / min in an injection volume of about 40 mL, and recombinant human hyaluronidase at a dose of about 500 U / mL.

[0355]

[0365] In any of the foregoing embodiments, the anti-amyloid β antibody or antigen-binding fragment thereof may be a full-length anti-amyloid β antibody.

[0356]

[0366] In some embodiments, the Alzheimer's disease is autosomal dominant Alzheimer's disease. In some embodiments, the autosomal dominant Alzheimer's disease is prodromal, mild, moderate, or mild to moderate. In some embodiments, the autosomal dominant Alzheimer's disease is mild to moderate. In some embodiments, the Alzheimer's disease is sporadic AD. In some embodiments, the Alzheimer's disease is early or mild AD.

[0357]

[0367] Any brain-targeting antibody or antigen-binding fragment thereof may be used in the methods, compositions and uses disclosed herein. In some embodiments, the brain-targeting antibody or antigen-binding fragment is an anti-amyloid beta antibody or antigen-binding fragment thereof disclosed herein. In some embodiments, the anti-amyloid beta antibody is crenezumab.

[0358]

[0368] In one aspect, the present disclosure provides a use of a composition for the preparation of a medicament for treating Alzheimer's disease in a subject, wherein the composition is suitable for subcutaneous administration and comprises a brain-targeting antibody or antigen-binding fragment thereof, wherein the brain-targeting antibody or antigen-binding fragment thereof is at a concentration of about 130 mg / mL to about 200 mg / mL. In some embodiments, the brain-targeting antibody or antigen-binding fragment thereof is an anti-amyloid beta antibody or antigen-binding fragment thereof disclosed herein. In some embodiments, the anti-amyloid beta antibody is crenezumab.

[0359]

[0369] In one aspect, the present disclosure provides a use of a composition for the preparation of a medicament for treating a subject at risk for Alzheimer's disease, wherein the composition is suitable for subcutaneous administration and comprises a brain-targeting antibody or antigen-binding fragment thereof, wherein the brain-targeting antibody or antigen-binding fragment thereof is at a concentration of about 130 mg / mL to about 200 mg / mL. In some embodiments, the brain-targeting antibody or antigen-binding fragment thereof is an anti-amyloid beta antibody or antigen-binding fragment thereof disclosed herein. In some embodiments, the anti-amyloid beta antibody is crenezumab.

[0360]

[0370] In one aspect, the present disclosure provides a use of the composition for the preparation of a medicament for treating cognitive impairment in a subject, wherein the composition is suitable for subcutaneous administration and comprises a brain-targeting antibody or antigen-binding fragment thereof, wherein the brain-targeting antibody or antigen-binding fragment thereof is at a concentration of about 130 mg / mL to about 200 mg / mL. In some embodiments, the brain-targeting antibody or antigen-binding fragment is an anti-amyloid beta antibody or antigen-binding fragment thereof disclosed herein. In some embodiments, the anti-amyloid beta antibody is crenezumab. In some embodiments, the cognitive impairment is mild cognitive impairment (MCI). In some embodiments, the subject is suffering from Alzheimer's disease.

[0361]

[0371] In one aspect, the present disclosure provides a use of the composition for the preparation of a medicament for reducing cognitive impairment in a subject, wherein the composition is suitable for subcutaneous administration and comprises a brain-targeting antibody or antigen-binding fragment thereof, wherein the brain-targeting antibody or antigen-binding fragment thereof is at a concentration of about 130 mg / mL to about 200 mg / mL. In some embodiments, the cognitive impairment is mild cognitive impairment (MCI). In some embodiments, the brain-targeting antibody or antigen-binding fragment is an anti-amyloid beta antibody or antigen-binding fragment thereof disclosed herein. In some embodiments, the anti-amyloid beta antibody is crenezumab. In some embodiments, the cognitive impairment is mild cognitive impairment (MCI). In some embodiments, the subject is suffering from Alzheimer's disease.

[0362]

[0372] In one aspect, the present disclosure provides a use of a composition for the preparation of a medicament for delaying the progression of cognitive impairment in a subject, wherein the composition is suitable for subcutaneous administration and comprises a brain-targeting antibody or antigen-binding fragment thereof, wherein the brain-targeting antibody or antigen-binding fragment thereof is at a concentration of about 130 mg / mL to about 200 mg / mL. In some embodiments, the brain-targeting antibody or antigen-binding fragment is an anti-amyloid beta antibody or antigen-binding fragment thereof disclosed herein. In some embodiments, the anti-amyloid beta antibody is crenezumab. In some embodiments, the cognitive impairment is mild cognitive impairment (MCI). In some embodiments, the subject is suffering from Alzheimer's disease.

[0363]

[0373] In one aspect, the present disclosure provides a use of a composition for the preparation of a medicament for treating early or mild to moderate AD without increasing the risk of adverse events, wherein the composition is suitable for subcutaneous administration and comprises a brain-targeting antibody or antigen-binding fragment thereof, wherein the brain-targeting antibody or antigen-binding fragment thereof is at a concentration of about 130 mg / mL to about 200 mg / mL. In some embodiments, the brain-targeting antibody or antigen-binding fragment thereof is an anti-amyloid beta antibody or antigen-binding fragment thereof disclosed herein. In some embodiments, the anti-amyloid beta antibody is crenezumab.

[0364]

[0374] In one aspect, the present disclosure provides a use of a composition for the preparation of a medicament for delaying the progression of Alzheimer's disease (AD) in a patient diagnosed with early or mild-to-moderate AD, wherein the composition is suitable for subcutaneous administration and comprises a brain-targeting antibody or antigen-binding fragment thereof, wherein the brain-targeting antibody or antigen-binding fragment thereof is at a concentration of about 130 mg / mL to about 200 mg / mL. In some embodiments, the brain-targeting antibody or antigen-binding fragment thereof is an anti-amyloid beta antibody or antigen-binding fragment thereof disclosed herein. In some embodiments, the anti-amyloid beta antibody is crenezumab.

[0365]

[0375] In one aspect, the present disclosure provides a use of a composition for the preparation of a medicament for delaying clinical deterioration in a patient diagnosed with early or mild-to-moderate Alzheimer's disease (AD), wherein the composition is suitable for subcutaneous administration and comprises a brain-targeting antibody or antigen-binding fragment thereof, wherein the brain-targeting antibody or antigen-binding fragment thereof is at a concentration of about 130 mg / mL to about 200 mg / mL. In some embodiments, the brain-targeting antibody or antigen-binding fragment thereof is an anti-amyloid beta antibody or antigen-binding fragment thereof disclosed herein. In some embodiments, the anti-amyloid beta antibody is crenezumab.

[0366]

[0376] In some embodiments, the disclosure provides for the use of a first dose and a second dose in the manufacture of one or more medicaments for treating Alzheimer's disease in a subject, wherein (a) the first dose comprises about 1700 mg of a brain-targeting antibody or antigen-binding fragment thereof and is suitable for subcutaneous administration at a flow rate of about 4 mL / min in an injection volume of 10 mL; and (b) the second dose comprises about 3400 mg of the brain-targeting antibody or antigen-binding fragment thereof and is suitable for subcutaneous administration at a flow rate of about 4 mL / min in an injection volume of 40 mL.

[0367]

[0377] In some embodiments, the disclosure provides for the use of a first dose and a second dose in the manufacture of one or more medicaments for treating Alzheimer's disease in a subject, wherein (a) the first dose comprises about 1700 mg of a brain-targeting antibody or antigen-binding fragment thereof and is suitable for subcutaneous administration at a flow rate of about 2 mL / min in an injection volume of 10 mL; and (b) the second dose comprises about 3400 mg of the brain-targeting antibody or antigen-binding fragment thereof and is suitable for subcutaneous administration at a flow rate of about 2 mL / min in an injection volume of 20 mL.

[0368]

[0378] In some embodiments, the disclosure provides for the use of a first dose and a second dose in the manufacture of one or more medicaments for treating Alzheimer's disease in a subject, (a) a first dose comprising about 3400 mg of a brain-targeting antibody or antigen-binding fragment thereof and suitable for subcutaneous administration at a flow rate of about 4 mL / min in an injection volume of 20 mL; said first dose is for co-administration with a permeation enhancer (e.g., hyaluronidase, including recombinant human hyaluronidase) at a dose of about 2000 U / mL; (b) a second dose comprising about 6800 mg of a brain-targeting antibody or antigen-binding fragment thereof and suitable for subcutaneous administration at a flow rate of about 4 mL / min in an injection volume of 40 mL; said second dose is for co-administration with a permeation enhancer (e.g., hyaluronidase, including recombinant human hyaluronidase) at a dose of about 1000 U / mL.

[0369]

[0379] In some embodiments, the disclosure provides for the use of a first dose and a second dose in the manufacture of one or more medicaments for treating Alzheimer's disease in a subject, wherein (a) the first dose comprises about 1700 mg of a brain-targeting antibody or antigen-binding fragment thereof and is suitable for subcutaneous administration at a flow rate of about 4 mL / min in an injection volume of 10 mL; and (b) the second dose comprises about 3400 mg of the brain-targeting antibody or antigen-binding fragment thereof and is suitable for subcutaneous administration at a flow rate of about 4 mL / min in an injection volume of 40 mL.

[0370]

[0380] In some embodiments, the disclosure provides for the use of a first dose and a second dose in the manufacture of one or more medicaments for treating Alzheimer's disease in a subject, (a) the first dose comprises about 3400 mg of a brain-targeting antibody or antigen-binding fragment thereof, in an injection volume of 20 mL, suitable for subcutaneous administration at a flow rate of about 4 mL / min; (b) the second dose comprises about 6800 mg of a brain-targeting antibody or antigen-binding fragment thereof and is suitable for subcutaneous administration in an injection volume of 40 mL at a flow rate of about 4 mL / min; said second dose is co-administered with a permeation enhancer (e.g., hyaluronidase, including recombinant human hyaluronidase) at a dose of about 500 U / mL.

[0371]

[0381] In some embodiments, the disclosure provides for the use of a first dose and a second dose in the manufacture of one or more medicaments for treating Alzheimer's disease in a subject, (a) a first dose comprises about 3400 mg of a brain-targeting antibody or antigen-binding fragment thereof and is suitable for subcutaneous administration at a flow rate of about 4 mL / min in an injection volume of 20 mL; said first dose is co-administered with a permeation enhancer (e.g., hyaluronidase, including recombinant human hyaluronidase) at a dose of about 2000 U / mL; (b) a second dose comprising about 6800 mg of a brain-targeting antibody or antigen-binding fragment thereof and suitable for subcutaneous administration at a flow rate of about 4 mL / min in an injection volume of 40 mL; said second dose is for co-administration with a permeation enhancer (e.g., hyaluronidase, including recombinant human hyaluronidase) at a dose of about 500 U / mL.

[0372]

[0382] In some embodiments, the disclosure provides for the use of a composition comprising about 6800 mg of a brain-targeting antibody or antigen-binding fragment thereof in the manufacture of a medicament for treating Alzheimer's disease in a subject, wherein the medicament is suitable for subcutaneous administration to a subject at a flow rate of about 4 mL / min with an injection volume of 40 mL; and the medicament is suitable for co-administration of the brain-targeting antibody or antigen-binding fragment thereof with a dose of about 500 U / mL of a permeation enhancer (e.g., hyaluronidase, including recombinant human hyaluronidase).

[0373]

[0383] In some embodiments, the disclosure provides for the use of a first dose and a second dose in the manufacture of one or more medicaments for treating a cognitive disorder in a subject, wherein (a) the first dose comprises about 1700 mg of a brain-targeting antibody or antigen-binding fragment thereof and is suitable for subcutaneous administration at a flow rate of about 4 mL / min in an injection volume of 10 mL; and (b) the second dose comprises about 3400 mg of the brain-targeting antibody or antigen-binding fragment thereof and is suitable for subcutaneous administration at a flow rate of about 4 mL / min in an injection volume of 40 mL.

[0374]

[0384] In some embodiments, the disclosure provides for the use of a first dose and a second dose in the manufacture of one or more medicaments for treating a cognitive disorder in a subject, wherein (a) the first dose comprises about 1700 mg of a brain-targeting antibody or antigen-binding fragment thereof and is suitable for subcutaneous administration at a flow rate of about 2 mL / min in an injection volume of 10 mL; and (b) the second dose comprises about 3400 mg of the brain-targeting antibody or antigen-binding fragment thereof and is suitable for subcutaneous administration at a flow rate of about 2 mL / min in an injection volume of 20 mL.

[0375]

[0385] In some embodiments, the disclosure provides for the use of a first dose and a second dose in the manufacture of one or more medicaments for treating a cognitive impairment in a subject, (a) a first dose comprising about 3400 mg of a brain-targeting antibody or antigen-binding fragment thereof and suitable for subcutaneous administration at a flow rate of about 4 mL / min in an injection volume of 20 mL; said first dose is for co-administration with a permeation enhancer (e.g., hyaluronidase, including recombinant human hyaluronidase) at a dose of about 2000 U / mL; (b) a second dose comprising about 6800 mg of a brain-targeting antibody or antigen-binding fragment thereof and suitable for subcutaneous administration at a flow rate of about 4 mL / min in an injection volume of 40 mL; said second dose is for co-administration with a permeation enhancer (e.g., hyaluronidase, including recombinant human hyaluronidase) at a dose of about 1000 U / mL.

[0376]

[0386] In some embodiments, the disclosure provides for the use of a first dose and a second dose in the manufacture of one or more medicaments for treating a cognitive disorder in a subject, wherein (a) the first dose comprises about 1700 mg of a brain-targeting antibody or antigen-binding fragment thereof and is suitable for subcutaneous administration at a flow rate of about 4 mL / min in an injection volume of 10 mL; and (b) the second dose comprises about 3400 mg of the brain-targeting antibody or antigen-binding fragment thereof and is suitable for subcutaneous administration at a flow rate of about 4 mL / min in an injection volume of 40 mL.

[0377]

[0387] In some embodiments, the disclosure provides for the use of a first dose and a second dose in the manufacture of one or more medicaments for treating a cognitive impairment in a subject, (a) the first dose comprises about 3400 mg of a brain-targeting antibody or antigen-binding fragment thereof, in an injection volume of 20 mL, suitable for subcutaneous administration at a flow rate of about 4 mL / min; (b) the second dose comprises about 6800 mg of a brain-targeting antibody or antigen-binding fragment thereof and is suitable for subcutaneous administration in an injection volume of 40 mL at a flow rate of about 4 mL / min; said second dose is co-administered with a permeation enhancer (e.g., hyaluronidase, including recombinant human hyaluronidase) at a dose of about 500 U / mL.

[0378]

[0388] In some embodiments, the disclosure provides for the use of a first dose and a second dose in the manufacture of one or more medicaments for treating a cognitive impairment in a subject, (a) a first dose comprises about 3400 mg of a brain-targeting antibody or antigen-binding fragment thereof and is suitable for subcutaneous administration at a flow rate of about 4 mL / min in an injection volume of 20 mL; said first dose is co-administered with a permeation enhancer (e.g., hyaluronidase, including recombinant human hyaluronidase) at a dose of about 2000 U / mL; (b) a second dose comprising about 6800 mg of a brain-targeting antibody or antigen-binding fragment thereof, suitable for subcutaneous administration at a flow rate of about 4 mL / min in an injection volume of 40 mL; said second dose is for co-administration with a permeation enhancer (e.g., hyaluronidase, including recombinant human hyaluronidase) at a dose of about 500 U / mL.

[0379]

[0389] In some embodiments, the disclosure provides for the use of a composition comprising about 6800 mg of a brain-targeting antibody or antigen-binding fragment thereof in the manufacture of a medicament for treating a cognitive disorder in a subject, wherein the medicament is suitable for subcutaneous administration to a subject at a flow rate of about 4 mL / min with an injection volume of 40 mL; and the medicament is suitable for co-administration of the brain-targeting antibody or antigen-binding fragment thereof with a dose of about 500 U / mL of a permeation enhancer (e.g., hyaluronidase, including recombinant human hyaluronidase).

[0380]

[0390] In some embodiments, the disclosure provides for the use of a first dose and a second dose in the manufacture of one or more medicaments for treating a subject at risk for Alzheimer's disease, wherein (a) the first dose comprises about 1700 mg of a brain-targeting antibody or antigen-binding fragment thereof and is suitable for subcutaneous administration at a flow rate of about 4 mL / min in an injection volume of 10 mL; and (b) the second dose comprises about 3400 mg of the brain-targeting antibody or antigen-binding fragment thereof and is suitable for subcutaneous administration at a flow rate of about 4 mL / min in an injection volume of 40 mL.

[0381]

[0391] In some embodiments, the disclosure provides for the use of a first dose and a second dose in the manufacture of one or more medicaments for treating a subject at risk for Alzheimer's disease, wherein (a) the first dose comprises about 1700 mg of a brain-targeting antibody or antigen-binding fragment thereof and is suitable for subcutaneous administration at a flow rate of about 2 mL / min in an injection volume of 10 mL; and (b) the second dose comprises about 3400 mg of a brain-targeting antibody or antigen-binding fragment thereof and is suitable for subcutaneous administration at a flow rate of about 2 mL / min in an injection volume of 20 mL.

[0382]

[0392] In some embodiments, the disclosure provides for the use of a first dose and a second dose in the manufacture of one or more medicaments for treating a subject at risk for Alzheimer's disease, (a) a first dose comprising about 3400 mg of a brain-targeting antibody or antigen-binding fragment thereof and suitable for subcutaneous administration at a flow rate of about 4 mL / min in an injection volume of 20 mL; said first dose is for co-administration with a permeation enhancer (e.g., hyaluronidase, including recombinant human hyaluronidase) at a dose of about 2000 U / mL; (b) a second dose comprising about 6800 mg of a brain-targeting antibody or antigen-binding fragment thereof and suitable for subcutaneous administration at a flow rate of about 4 mL / min in an injection volume of 40 mL; said second dose is for co-administration with a permeation enhancer (e.g., hyaluronidase, including recombinant human hyaluronidase) at a dose of about 1000 U / mL.

[0383]

[0393] In some embodiments, the disclosure provides for the use of a first dose and a second dose in the manufacture of one or more medicaments for treating a subject at risk for Alzheimer's disease, wherein (a) the first dose comprises about 1700 mg of a brain-targeting antibody or antigen-binding fragment thereof and is suitable for subcutaneous administration at a flow rate of about 4 mL / min in an injection volume of 10 mL; and (b) the second dose comprises about 3400 mg of the brain-targeting antibody or antigen-binding fragment thereof and is suitable for subcutaneous administration at a flow rate of about 4 mL / min in an injection volume of 40 mL.

[0384]

[0394] In some embodiments, the disclosure provides for the use of a first dose and a second dose in the manufacture of one or more medicaments for treating a subject at risk for Alzheimer's disease, (a) the first dose comprises about 3400 mg of a brain-targeting antibody or antigen-binding fragment thereof, in an injection volume of 20 mL, suitable for subcutaneous administration at a flow rate of about 4 mL / min; (b) the second dose comprises about 6800 mg of a brain-targeting antibody or antigen-binding fragment thereof and is suitable for subcutaneous administration in an injection volume of 40 mL at a flow rate of about 4 mL / min; said second dose is co-administered with a permeation enhancer (e.g., hyaluronidase, including recombinant human hyaluronidase) at a dose of about 500 U / mL.

[0385]

[0395] In some embodiments, the disclosure provides for the use of a first dose and a second dose in the manufacture of one or more medicaments for treating a subject at risk for Alzheimer's disease, (a) a first dose comprises about 3400 mg of a brain-targeting antibody or antigen-binding fragment thereof and is suitable for subcutaneous administration at a flow rate of about 4 mL / min in an injection volume of 20 mL; said first dose is co-administered with a permeation enhancer (e.g., hyaluronidase, including recombinant human hyaluronidase) at a dose of about 2000 U / mL; (b) a second dose comprising about 6800 mg of a brain-targeting antibody or antigen-binding fragment thereof and suitable for subcutaneous administration at a flow rate of about 4 mL / min in an injection volume of 40 mL; said second dose is for co-administration with a permeation enhancer (e.g., hyaluronidase, including recombinant human hyaluronidase) at a dose of about 500 U / mL.

[0386]

[0396] In some embodiments, the disclosure provides for the use of a composition comprising about 6800 mg of a brain-targeting antibody or antigen-binding fragment thereof in the manufacture of a medicament for treating a subject at risk for Alzheimer's disease, wherein the medicament is suitable for subcutaneous administration to a subject at a flow rate of about 4 mL / min with an injection volume of 40 mL; and the medicament is suitable for co-administration of the brain-targeting antibody or antigen-binding fragment thereof with a dose of about 500 U / mL of a permeation enhancer (e.g., hyaluronidase, including recombinant human hyaluronidase).

[0387]

[0397] In some embodiments, the disclosure provides for the use of a first dose and a second dose in the manufacture of one or more medicaments for reducing cognitive impairment in a subject, wherein (a) the first dose comprises about 1700 mg of a brain-targeting antibody or antigen-binding fragment thereof and is suitable for subcutaneous administration at a flow rate of about 4 mL / min in an injection volume of 10 mL; and (b) the second dose comprises about 3400 mg of the brain-targeting antibody or antigen-binding fragment thereof and is suitable for subcutaneous administration at a flow rate of about 4 mL / min in an injection volume of 40 mL.

[0388]

[0398] In some embodiments, the disclosure provides for the use of a first dose and a second dose in the manufacture of one or more medicaments for reducing cognitive impairment in a subject, wherein (a) the first dose comprises about 1700 mg of a brain-targeting antibody or antigen-binding fragment thereof and is suitable for subcutaneous administration at a flow rate of about 2 mL / min in an injection volume of 10 mL; and (b) the second dose comprises about 3400 mg of the brain-targeting antibody or antigen-binding fragment thereof and is suitable for subcutaneous administration at a flow rate of about 2 mL / min in an injection volume of 20 mL.

[0389]

[0399] In some embodiments, the disclosure provides for the use of a first dose and a second dose in the manufacture of one or more medicaments for reducing cognitive impairment in a subject, (a) a first dose comprising about 3400 mg of a brain-targeting antibody or antigen-binding fragment thereof and suitable for subcutaneous administration at a flow rate of about 4 mL / min in an injection volume of 20 mL; said first dose is for co-administration with a permeation enhancer (e.g., hyaluronidase, including recombinant human hyaluronidase) at a dose of about 2000 U / mL; (b) a second dose comprising about 6800 mg of a brain-targeting antibody or antigen-binding fragment thereof and suitable for subcutaneous administration at a flow rate of about 4 mL / min in an injection volume of 40 mL; said second dose is for co-administration with a permeation enhancer (e.g., hyaluronidase, including recombinant human hyaluronidase) at a dose of about 1000 U / mL.

[0390]

[0400] In some embodiments, the disclosure provides for the use of a first dose and a second dose in the manufacture of one or more medicaments for reducing cognitive impairment in a subject, wherein (a) the first dose comprises about 1700 mg of a brain-targeting antibody or antigen-binding fragment thereof and is suitable for subcutaneous administration at a flow rate of about 4 mL / min in an injection volume of 10 mL; and (b) the second dose comprises about 3400 mg of the brain-targeting antibody or antigen-binding fragment thereof and is suitable for subcutaneous administration at a flow rate of about 4 mL / min in an injection volume of 40 mL.

[0391]

[0401] In some embodiments, the disclosure provides for the use of a first dose and a second dose in the manufacture of one or more medicaments for reducing cognitive impairment in a subject, (a) the first dose comprises about 3400 mg of a brain-targeting antibody or antigen-binding fragment thereof, in an injection volume of 20 mL, suitable for subcutaneous administration at a flow rate of about 4 mL / min; (b) the second dose comprises about 6800 mg of a brain-targeting antibody or antigen-binding fragment thereof and is suitable for subcutaneous administration in an injection volume of 40 mL at a flow rate of about 4 mL / min; said second dose is co-administered with a permeation enhancer (e.g., hyaluronidase, including recombinant human hyaluronidase) at a dose of abo...

Claims

A medicament for treating Alzheimer's disease in a subject or for treating a subject at risk of Alzheimer's disease, comprising a composition comprising a brain-targeted antibody or an antigen-binding fragment thereof, wherein the composition is administered subcutaneously to the subject, and the brain-targeted antibody or an antigen-binding fragment thereof is at a concentration of from about 130 mg / mL to about 200 mg / mL. A medicament for treating early or mild to moderate AD without increasing the risk of adverse events, comprising a composition comprising a brain-targeted antibody or an antigen-binding fragment thereof, wherein the composition is administered subcutaneously to the subject, and the brain-targeted antibody or an antigen-binding fragment thereof is at a concentration of from about 130 mg / mL to about 200 mg / mL. A medicament for delaying the progression of AD in a subject diagnosed with early or mild to moderate Alzheimer's disease (AD), comprising a composition comprising a brain-targeted antibody or an antigen-binding fragment thereof, wherein the composition is administered subcutaneously to the subject, and the brain-targeted antibody or an antigen-binding fragment thereof is at a concentration of from about 130 mg / mL to about 200 mg / mL.

4. The medicament according to claim 1, wherein the brain-targeted antibody or an antigen-binding fragment thereof is administered at a dose between about 400 mg and about 7500 mg.

5. The medicament according to claim 1, wherein the brain-targeted antibody or an antigen-binding fragment thereof is administered at an injection volume of from about 4 mL to about 60 mL. The medicament according to claim 1, wherein a permeation enhancer is administered to the subject.

7. The medicament according to claim 6, wherein the permeation enhancer is recombinant human hyaluronidase.

8. The medicament according to claim 7, wherein the recombinant human hyaluronidase is at a concentration of from about 300 U / mL to about 2200 U / mL.

9. The medicament according to claim 1, wherein the Alzheimer's disease is autosomal dominant Alzheimer's disease.

10. The medicament according to claim 9, wherein the autosomal dominant Alzheimer's disease is in the prodromal, mild, moderate, or mild to moderate stage.

11. The medicament according to claim 1, wherein the brain-targeted antibody is an anti-amyloid β antibody.

12. A composition comprising from about 400 mg to about 7500 mg of an anti-amyloid β antibody or an antigen-binding fragment thereof.

13. The composition according to claim 12, further comprising recombinant human hyaluronidase.

14. A composition comprising an anti-amyloid β antibody or an antigen-binding fragment thereof at a concentration of from about 130 mg / mL to about 200 mg / mL.

Images