Anti-lag-3 antibodies to treat hematological malignancies

A LAG-3, malignant tumor technology, applied in the direction of antibodies, anti-tumor drugs, antibody medical components, etc., can solve the problems of not binding to class II MHC and unknown functions

Pending Publication Date: 2016-10-05
BRISTOL MYERS SQUIBB CO
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

LAG-3 can also occur as a soluble protein, but it does not bind MHC class II and its function is unknown

Method used

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  • Anti-lag-3 antibodies to treat hematological malignancies
  • Anti-lag-3 antibodies to treat hematological malignancies
  • Anti-lag-3 antibodies to treat hematological malignancies

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0112] Example 1: Preclinical Pharmacology of Anti-LAG-3 Antibody (BMS-986016)

[0113] Anti-LAG-3 antibody, BMS-986016

[0114] BMS-986016 is a fully human antibody specific for human LAG-3, isolated from immunized transgenic mice expressing human immunoglobulin genes. It is expressed as an IgG4 isotype antibody and contains a stabilizing hinge mutation (S228P) to attenuate Fc receptor binding to reduce or exclude the possibility of antibody- or complement-mediated killing of target cells. The heavy chain and light chain amino acid sequences of BMS-986016 are set forth in SEQ ID NO: 1 and 2, respectively.

[0115] The ability of BMS-986016 to bind recombinant human LAG-3 antigen was determined using Biacore and enzyme-linked immunosorbent assay (ELISA). Binding to human and primate LAG-3+ transfectants and to activated human or primate T cells was measured using flow cytometry and Scatchard analysis. BMS-986016 with high affinity (K D = 0.12-0.5 nM) binds to human LAG-3...

Embodiment 2

[0116] Example 2: Toxicity of anti-LAG-3 antibody (BMS-986016)

[0117] The following preclinical toxicology studies were performed:

[0118] A. A GLP-compliant 4-week intravenous combination toxicity study of BMS-986016 and nivolumab in macaques with a 6-week recovery period

[0119] The relevant results of single agent treatment with BMS-986016 are as follows:

[0120] 1. Single agent BMS-986016 administered up to 100 mg / kg / week produced no adverse changes.

[0121] 2. The NOAEL of single agent BMS-986016 is considered to be 100 mg / kg / week (mean AUC[0-168h]=474,000 μg·h / mL). The dose administered (100 mg / kg BMS-986016) was > 10 times the maximum dose suggested by the current study.

[0122] B. GLP-compliant tissue cross-reactivity study of BMS-986016 in human and selected macaque tissues

[0123] The relevant results for cross-reactivity are as follows:

[0124] 1. Positive staining with BMS-986016-FITC was observed in the plasma membrane or plasma membrane granules of ...

Embodiment 3

[0131] Example 3: Preclinical Metabolism and Pharmacokinetics of Anti-LAG-3 Antibody (BMS-986016)

[0132] Metabolism studies of BMS-986016 in animals have not been performed in accordance with regulatory guidelines for biotechnology-derived pharmaceuticals (ICH Harmonized Tripartite Guideline, S6(R1) Preclinical Safety Evaluation of Biotechnology-Derived Pharmaceuticals. International Conference on Harmonization, 2011). Monoclonal antibodies (mAbs) are expected to be degraded into small peptides and amino acids in vivo via biochemical pathways independent of cytochrome P450 enzymes.

[0133] BMS-986016 demonstrated favorable pharmacokinetic (PK) properties in rhesus monkeys. From both single-dose and repeat-dose IV PK studies, BMS-986016 decays in a bi-exponential manner and exposure is approximately dose-proportional. Systemic clearance (CLTp) varied from 0.12 to 0.22 mL / h / kg, and terminal half-life (T-HALF) varied from 133 to 414 hours. The volume of distribution (Vss) at...

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Abstract

Provided are methods for clinical treatment of hematological malignancies, such as relapsed or refractory chronic lymphocytic leukemia or lymphoma using an anti-LAG-3 antibody. Particular malignancies include, e.g., chronic lymphocytic leukemia (CLL), Hodgkin lymphoma (HL), or non-Hodgkin lymphoma (NHL).

Description

[0001] Cross References to Related Applications [0002] This application claims priority and benefit to U.S. Provisional Patent Application No. 61 / 932,589, filed January 28, 2014, which is incorporated herein in its entirety. Background of the invention [0003] Lymphocyte activation gene-3 (LAG-3; CD223) is an activated CD4 + and CD8 + Type I transmembrane proteins expressed on the cell surface of T cells as well as NK and dendritic cell subsets (Triebel F et al., J. Exp. Med. 1990; 171:1393-1405; Workman CJ et al., J. Immunol. 2009; 182(4):1885-91). LAG-3 is closely related to CD4, a co-receptor for T helper cell activation. Both molecules possess four extracellular Ig-like domains, and both require binding of their ligand, class II major histocompatibility complex (MHC), for their functional activity. Unlike CD4, LAG-3 is only expressed on the cell surface of activated T cells, and its cleavage from the cell surface terminates LAG-3 signaling. LAG-3 can also occur as ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K39/395A61P35/00A61P35/02
CPCC07K16/2803A61K2039/505C07K2317/92C07K2317/565C07K2317/56C07K2317/21A61P35/00A61P35/02A61P35/04A61P37/04C07K2317/73A61K2039/545C07K2317/53C07K2317/71C07K2317/75
Inventor A·A·古铁雷斯J·格罗索C·M·希尔M·塞尔比K·E·路易斯
Owner BRISTOL MYERS SQUIBB CO
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