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Endothelial lipase antibodies for treatment of cardiovascular diseases

A cardiovascular and antibody technology, applied in the direction of antibodies, antibody medical components, anti-enzyme immunoglobulin, etc.

Pending Publication Date: 2022-06-21
MEDIMMUNE LLC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, there are currently no approved therapies that target EL or adequately reduce CV risk

Method used

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  • Endothelial lipase antibodies for treatment of cardiovascular diseases
  • Endothelial lipase antibodies for treatment of cardiovascular diseases
  • Endothelial lipase antibodies for treatment of cardiovascular diseases

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 2

[0235] MEDI5884 was administered to cynomolgus monkeys in a single-dose non-Good Laboratory Practice (GLP) PK / pharmacodynamic (PD) study and 2 repeat-dose GLP toxicology studies. Single doses of MEDI5884 administered subcutaneously (SC) up to 30 mg / kg were well tolerated. There were no unplanned deaths, adverse clinical observations, injection site reactions, or adverse effects on body weight. Following repeated SC dosing (dose every 2 weeks) with 10, 30 or 100 mg / kg / dose of MEDI5884 for 1 or 6 months, all animals survived until scheduled sacrifice. No MEDI5884-related changes were observed in clinical observations, ophthalmic evaluations, body weight, behavior, neurophysiology, respiratory rate, injection site irritation score, heart rate, electrocardiogram (ECG), or blood pressure. Treatment-related findings were limited to pharmacologically mediated minimal to moderate increases in TC, HDL-C, LDL-C, and phospholipids at all dose levels. Microscopically, the presence of mi...

Embodiment 3

[0237] MEDI5884 was evaluated in a Phase 1, first-in-human blinded, placebo-controlled, single-dose escalation (SDE) study to evaluate the safety of subcutaneous (SC) administration of MEDI5884 in healthy subjects not receiving statin therapy Sex, PK and PD. Subjects were randomized in a 3:1 ratio to receive 30, 100, 300, or 600 mg of MEDI5884 or placebo; the initial cohort of each dose level was 6 MEDI5884 and 2 placebo subjects. These cohorts were subsequently replicated with subjects of Japanese ancestry to provide data to support clinical studies in Japan. A total of 64 subjects were enrolled at US sites. The duration of follow-up for each cohort varied from 28 days to 90 days after dosing.

[0238] Subjects received a single injection of MEDI5884 (or placebo) at doses of 30 and 100 mg, 3 SC injections of 300 mg dose (100 mg each) or 6 SC injections of 600 mg dose (100 mg each).

[0239] subjects

[0240] The median (SD) age of enrolled subjects was 35.9(9) years; 93...

Embodiment 6

[0315] A combined pharmacology study was performed to evaluate the effect of inhibition of proprotein convertase subtilisin / kexin type 9 (PCSK9) on lipoprotein metabolism following MEDI5884 treatment. The research program is in Figure 9 described in. To better simulate a hypothetical patient population already treated with LDL-C-lowering drugs, healthy cynomolgus monkeys were first given weekly subcutaneous injections of a PCSK9 neutralizing monoclonal antibody (mAb) (10 mg / kg; n=8) or Vehicle, starting on day 0, continued for four weeks to establish a baseline of low LDL-C. The PCSK9 mAb used was HS9 (comprising the VH and VL sequences of SEQ ID NO: 14 and 15, respectively). The HS9 antibody (in the context of the GLP-1 fusion protein known as MEDI4166) is disclosed in Chodorge et al., Sci. Rep. 8:17545 (2018) and International PCT Publication No. WO2015127273, each of which is incorporated by reference in its entirety and into this article.

[0316] Then on day 28 ( F...

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Abstract

The present disclosure provides methods of administering antibodies and antigen-binding fragments thereof that specifically bind to human endothelial lipase (EL) to a subject in need thereof, e.g., a subject having cardiovascular disease.

Description

[0001] Cross References to Related Applications [0002] This application claims U.S. Provisional Application No. 63 / 104,410, filed October 22, 2020, U.S. Provisional Application No. 62 / 940,164, filed November 25, 2019, and U.S. Provisional Application No. 62 / 932,257, filed November 7, 2019 interests, each of which is incorporated herein by reference in its entirety. 1. Technical field [0003] The present disclosure relates generally to methods of treating diseases or disorders, such as cardiovascular diseases and disorders, using antibodies and antigen-binding fragments thereof that specifically bind human endothelial lipase (EL). Advantageous dosing regimens are provided. 2. Background technology [0004] Endothelial lipase (EL) is a circulating phospholipase that has been recognized as a member of the triglyceride lipase family. EL possesses both phospholipase and triglyceride lipase activities, and it hydrolyzes high-density lipoprotein (HDL) more efficiently than oth...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K39/00A61K39/395A61K9/08
CPCA61K9/0019C07K2317/24C07K2317/76A61K2039/505C07K16/40A61K2039/545C07K2317/33A61K2039/507C07K2317/90A61P9/10
Inventor J.S.格里姆斯比C-Y.金J.法卢恩J.A.西亚S.K.卡拉塔纳西斯R.T.小乔治J.E.勒雷B.T.哈默Y.黄A.I.罗森鲍姆
Owner MEDIMMUNE LLC
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