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Subcutaneous dosing of Anti-cd38 antibodies

A technology for subcutaneous administration of antibodies, applied in the direction of antibodies, anti-tumor drugs, antibody medical components, etc., can solve problems such as severe infusion-related reactions

Pending Publication Date: 2020-12-29
TAKEDA PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In addition, intravenous administration of therapeutic monoclonal antibodies can lead to severe infusion-related reactions (IRR)

Method used

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  • Subcutaneous dosing of Anti-cd38 antibodies
  • Subcutaneous dosing of Anti-cd38 antibodies
  • Subcutaneous dosing of Anti-cd38 antibodies

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0339] Example 1: Model-Based Characterization of Anti-CD38 Antibodies in Cynomolgus Monkeys

[0340] The anti-CD38 antibody AB79 binds to cynomolgus monkey (cyno) CD38, thereby rendering it incompatible with Daratumumab (Darzalex TM ) (a cytolytic CD38 monoclonal antibody recently approved for the treatment of multiple myeloma). This unique capability supports the use of cynomolgus monkeys in preclinical studies to characterize AB79 pharmacokinetics (PK), pharmacodynamics (PD), and safety. To this end, assays were developed to measure drug concentration, immunogenicity and quantify T cells, B cells and NK lymphocytes in the blood of cynomolgus monkeys. These parameters were evaluated in eight pharmacological and toxicological preclinical studies. Among the cell populations tested, CD38 expression was highest on NK cells; therefore, the drug effect on NK cells was assumed to be closest to that on the target cells considered, plasmablasts, plasma cells and other activated lym...

Embodiment 2

[0422] Example 2: AB79 depletes CD38+ cells

[0423] CD38 is a cADPR hydrolase expressed on human fibroblasts, plasma cells, NK cells and activated T and B cells, but not on mature platelets or erythrocytes based on AB79 binding. In patients with rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE), plasma cells and activated B and T cells may be important contributors to the disease. with targeting CD20 and not directly depleting CD20 低 / 阴性 Unlike other B-cell selective therapies for plasmablasts, CD38 is expressed at high levels on plasmablasts and plasma cells, making these cells a direct target of AB79. In vitro studies in human blood cells and cell lines showed that binding of AB79 to CD38 did not result in PBMC cytokine activation, thus demonstrating that AB79 is not an agonist, as discussed below. In contrast, AB79 mediated cell depletion of human B lineage cell lines via ADCC and CDC, and in most cases, cell lines with increased CD38 expression were more p...

Embodiment 3

[0446] Example 3: For the study of the safety, tolerability, efficacy, Phase 1 / 2a study of pharmacokinetics and immunogenicity

[0447] The purpose of this study is to evaluate safety, tolerability, pharmacokinetics (PK), immunogenicity, dose-limiting toxicity (DLT) and maximum tolerated dose (MTD) in Phase 1 of the study / recommended Phase 2 dose (RP2D), and provides a preliminary evaluation of the clinical activity of AB79 monotherapy in subjects with relapsed and / or refractory multiple myeloma (RRMM). The study included patients with RRMM previously treated with at least proteasome inhibitors (PIs), immunomodulatory drugs (IMids), alkylating agents and steroids. Patients should have refractory disease or be intolerant to at least 1 PI and at least 1 IMiD, and they should have received 3 or more prior therapies if one of those therapies included a combination of PI and IMiD , or have received at least 2 prior therapies. During the phase 1b dose escalation portion, prior ex...

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Abstract

Methods of administering isolated anti-CD38 antibodies subcutaneously are disclosed. The methods provide an effective treatment for autoimmune diseases and cancers, including hematologic diseases. Also disclosed are unit dosage forms for the anti-CD38 antibodies.

Description

[0001] Cross References to Related Applications [0002] This application claims the benefit of US Provisional Application No. 62 / 649,489 filed March 28, 2018, which is hereby incorporated by reference in its entirety. technical field [0003] Methods and compositions for administering isolated anti-CD38 antibodies via subcutaneous (SC) administration are disclosed. [0004] Background of the invention [0005] CD38 (also known as cyclic ADP ribohydrolase) is a type II transmembrane glycoprotein with a long C-terminal extracellular domain and a short N-terminal cytoplasmic domain. CD38 is a member of a group of related membrane-bound or soluble enzymes comprising CD157 and the Aplysia ADPR cyclase. This family of enzymes has the unique ability to convert NAD to cyclic ADP-ribose or nicotinic acid-adenine dinucleotide phosphate. CD38 is involved in Ca 2+ Mobilizes and participates in signal transduction through tyrosine phosphorylation of a number of signaling molecules, in...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K16/28C07K16/30A61P35/00
CPCC07K16/2896C07K16/30C07K2317/565C07K2317/732C07K2317/90A61K2039/505A61K2039/54A61K2039/545A61K2039/585A61P35/00A61K9/0019C07K16/3061
Inventor E·费迪克M·汉利A·帕卢姆伯
Owner TAKEDA PHARMA CO LTD
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