Search

EP-4740959-A2 - THERAPEUTIC USE OF LEVOROTATORY -LACTAMS IN HEMATOPOIESIS, IMMUNO-ONCOLOGY THERAPY, AND REGULATION OF LIPOPROTEIN AND APOLIPOPROTEIN LEVELS

EP4740959A2EP 4740959 A2EP4740959 A2EP 4740959A2EP-4740959-A2

Abstract

A method for increasing the number of CD4+ T-lymphocytes in the serum of a subject in need of such treatment comprising administering to the subject a pharmaceutical composition comprising an amount of an L-isomer of β-lactam effective to increase the number of CD4+ T-lymphocytes in said patient's serum.

Inventors

  • BRISTOW, CYNTHIA L.
  • WINSTON, RONALD

Assignees

  • Alpha-1 Biologics LLC

Dates

Publication Date
20260513
Application Date
20180118

Claims (6)

  1. A β-lactam composition for use in a method for treating a subject suffering from kidney cancer, the β-lactam composition comprising (a) an immune checkpoint inhibitor and (b) a β-lactam.
  2. The β-lactam composition for use in a method for treating a subject suffering from kidney cancer, wherein the method comprises administering the β-lactam composition to said subject in need of such treatment.
  3. The β-lactam composition for use in a method for treating a subject suffering from kidney cancer of claim 1 wherein the checkpoint inhibitor is an anti-PD-1 or anti PD-L1 monoclonal antibody.
  4. The β-lactam composition for use in a method for treating a subject suffering from kidney cancer of claim 1 wherein the amounts of (a) and (b) in combination are effective to treat said subject.
  5. The β-lactam composition for use in a method for treating a subject suffering from kidney cancer of claim 1 wherein said β-lactam is L-ampicillin or wherein said β-lactam is a salt of L-ampicillin.
  6. An L-isomer of a β-lactam for use in a method for treating a patient suffering from kidney cancer, wherein said β-lactam has substantially no bactericidal activity and is a tromethamine salt of L-ampicillin, and wherein in said method a therapeutically effective amount is administered to said patient.

Description

TECHNICAL FIELD This present invention relates to the use of levorotatory β-lactams in hematopoiesis, immune-oncology therapy, and the regulation of lipoprotein and apolipoprotein levels. BACKGROUND OF THE INVENTION Human leukocyte elastase (HLE, EC.3.4.21.37) is a serine proteinase that is synthesized and processed as a single molecular protein that is targeted exclusively for the cell surface (HLE-CS) early in ontogeny of lymphoid and myeloid cells when they are too immature to form granules. However, HLE is targeted for granule compartmentalization (HLE-G) later in ontogeny when cells develop the capability to form granules (Gullberg et al., 1995; Garwicz et al., 2005). Whereas HLE-G has enzymatic activity, HLE-CS acts as a receptor, and there is no evidence of its having enzymatic activity. The primary physiologic mechanism for controlling the enzymatic activity of HLE-G is the abundant proteinase inhibitor alpha-1 proteinase inhibitor (α1PI, α1 antitrypsin). When bound to HLE-G, a covalent-like complex is formed in which neither α1PI, nor HLE-G are cleaved (Dementiev et al., 2006). Similarly, when α1PI binds to HLE-CS, a complex is formed which does not appear to involve completion of enzymatic activity, and the complex induces polarization of functionally-related receptors and cell motility (Wolf et al., 2003). Functionally-related receptors include the chemokine receptor CXCR4 (CD184), CD4, and the T cell antigen receptor (TcR). In healthy individuals, 98% of α1PI is in the active form. Normal ranges are 18-53 µM active and 0-11 µM inactive α1PI (Bristow et al., 2001). Active α1PI circulates in blood in two isoforms in dynamic equilibrium: 1) native α1PI, which binds irreversibly to HLE-CS, and 2) thiol-modified α1PI, which binds reversibly to HLE-CS (Tyagi, 1991). Inactive α1PI arises during infection or inflammation via modification of active α1PI by factors released from microorganisms or host cells. Inactive α1PI can arise by complexing with HLE-G or HLE-CS, being cleaved by proteinases other than HLE, or oxygenation. In its inactivated form, α1PI binds to low density lipoprotein (LDL), apoB, and members of the LDL receptor family (LDL-RFMs), whereby α1PI facilitates LDL uptake into cells (Mashiba et al., 2001; Janciauskiene et al., 2001). Binding of active α1PI to HLE-CS at the leading edge of migrating cells induces aggregation and polarization of LDL-RFMs with other functionally-related receptors (Bristow et al., 2003; 2008; Bristow and Flood, 1993). Cellular locomotion repositions the HLE-CS complex including functionally-associated receptors to the trailing edge of the cell where LDL-RFMs on the same cell bind to the α1PI-HLE-CS complexes through an interaction that involves the α1PI C-terminal domain (C-36, VIRIP) (Kounnas et al., 1996; Janciauskiene el al., 2001). This interaction induces internalization (endocytosis) of LDL-RFMs including functionally-related receptors within the aggregate and entities bound to them such as lipoproteins and viruses. This action furthers retraction of the trailing edge of the migrating cell thereby promoting forward locomotion (Kounnas el al., 1996; Cao el al., 2006; Bristow et al., 2003; Bristow et al., 2013). The recycling of endocytosed receptors and polarization at the leading edge of a migrating cells followed by endocytosis at the trailing edge operates somewhat like a conveyor belt. If one of the components involved in this conveyor belt mechanism is missing or blocked, the cell halts migrating. For example, bacteria, snake bites, blood clotting, and most other non-normal situations produce non-normal proteases which cleave sentinel proteinase inhibitors including α1PI. When α1PI is inactivated, it can no longer bind its receptor HLE-CS. In the absence of α1PI-HLE-CS complexes, the LDL-RFMs are not triggered for endocytosis and this causes blood cells to stop migrating. This mechanistic process provides a method for locomoting immune cells to sample the environment for nutrients (e.g. lipoproteins and insulin-coupled glucose), toxic material (e.g. viruses, bacterial enzymes, inflammatory products), or inert material (e.g. recycled receptors). Due to the dynamics of the process, targeting HLE-CS using levorotatory β-lactams allows regulation of hematopoiesis, lipoprotein levels, and unwanted tissue degradation. Cell motility results from selective and sequential adherence and release produced by activation and deactivation of receptors (Wright and Meyer, 1986; Ali et al., 1996), consequent polar segregation of related membrane proteins to the leading edge or trailing uropod, and both clockwise and counterclockwise propagation of Ca++ waves which initiate from different locations in the cell (Kindzelskii and Petty, 2003). Thus, several aspects of the complex process may be quantitated. The most direct and most easily interpreted method for quantitating cell motility is the enumeration of adherent cells in response to a chemotactic agent such as α1PI.