# US 12,006,366 B2 · Methods and compositions for preventing type 1 diabetes

> Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt

- Number: US 12,006,366 B2
- Document ID: US12006366B2
- Status: Granted
- Kind: B2
- Application number: 17/345,495
- Filed: 2021-06-11
- Published: 2022-02-10
- Granted: 2024-06-11
- Earliest claimed: 2020-06-11
- Assignees: Provention Bio, Inc.; Yale University; Benaroya Research Institure at Virginia Mason
- Applicants: Provention Bio, Inc.
- Inventors: Francisco Leon; Kevan C. Herold; Sarah Alice Long; Peter S. Linsley
- Web page: https://patentgrep.com/patent/US12006366B2

## CPC

- C07K 16/2809: {against the T-cell receptor (TcR)-CD3 complex}
- G01N 33/5091: {for testing the pathological state of an organism}
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- G01N 33/6854: {Immunoglobulins}
- A61K 2039/505: {comprising antibodies}
- A61K 2039/545: {characterised by the dose, timing or administration schedule}
- G01N 2333/705: Assays involving receptors, cell surface antigens or cell surface determinants
- G01N 2333/7051: T-cell receptor (TcR)-CD3 complex
- G01N 2333/70517: CD8
- G01N 2800/042: Disorders of carbohydrate metabolism, e.g. diabetes, glucose metabolism
- G01N 2800/50: Determining the risk of developing a disease
- G01N 2800/52: Predicting or monitoring the response to treatment, e.g. for selection of therapy based on assay results in personalised medicine; Prognosis
- C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00)
- G01N: INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES (measuring or testing apparatus or processes other than immunoassay, involving enzymes or microorganisms C12M, C12Q)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)

## Abstract

Provided herein, in one aspect, is a method of preventing or delaying the onset of clinical type 1 diabetes (T1D), comprising: providing a non-diabetic subject who is at risk for T1D; administering a prophylactically effective amount of an anti-CD3 antibody to the non-diabetic subject; and determining, prior to or after the administering step, that the non-diabetic subject has more than about 5% to more than about 10% TIGIT+KLRG1+CD8+ T-cells in all CD3+ T cells, which is indicative of successful prevention or delay of the onset of clinical T1D.

## Claims

### Claim 1

A method of preventing or delaying the onset of clinical type 1 diabetes (T1D), comprising:
administering a prophylactically effective amount of teplizumab to a non-diabetic subject who is at risk for T1D, wherein the prophylactically effective amount of teplizumab comprises a 10 to 14 day course of teplizumab,
wherein at three months or more after the administration of the 10 to 14 day course of teplizumab, the subject has a frequency of from about 5% to about 50% T Cell Immunoreceptor With Ig And ITIM Domains (TIGIT)+ killer cell lectin like receptor G1 (KLRG1)+ cluster of differentiation 8 (CD8)+ T-cells in all cluster of differentiation 3 (CD3)+ T-cells, indicative of successful prevention or delay of the onset of clinical T1D.

### Claim 2 (depends on 1)

The method of claim 1, wherein the non-diabetic subject is a relative of a patient with T1D.

### Claim 3 (depends on 1)

The method of claim 1, wherein the non-diabetic subject (1) is negative for zinc transporter 8 (ZnT8) antibodies, (2) is HLA-DR4+, and/or (3) is not HLA-DR3+.

### Claim 4 (depends on 3)

The method of claim 3, wherein the non-diabetic subject has 2 or more diabetes-related autoantibodies selected from islet cell antibodies (ICA), insulin autoantibodies (IAA), and antibodies to glutamic acid decarboxylase (GAD), tyrosine phosphatase (IA-2/ICA512) or ZnT8.

### Claim 5 (depends on 3)

The method of claim 3, wherein the non-diabetic subject does not have antibodies against ZnT8.

### Claim 6 (depends on 3)

The method of claim 3, wherein the non-diabetic subject is HLA-DR4+ and is not HLA-DR3+.

### Claim 7 (depends on 1)

The method of claim 1, wherein the non-diabetic subject has abnormal glucose tolerance on oral glucose tolerance test (OGTT).

### Claim 8 (depends on 7)

The method of claim 7, wherein the abnormal glucose tolerance on OGTT is a fasting glucose level of 110-125 mg/dL, a 2 hour plasma glucose level of ≥140 and <200 mg/dL, or an intervening glucose level of >200 mg/dL at 30, 60, or 90 minutes on OGTT.

### Claim 9 (depends on 1)

The method of claim 1, comprising administering by subcutaneous injection the 10 to 14 day course of teplizumab at a daily dose of 10-1000 micrograms/meter squared (μg/m2).

### Claim 10 (depends on 1)

The method of claim 1, wherein the administering of the prophylactically effective amount of teplizumab delays median time to clinical diagnosis of T1D by at least 50%, at least 80%, or by at least 90%, or at least 12 months, at least 18 months, at least 24 months, at least 36 months, at least 48 months, or at least 60 months.

### Claim 11 (depends on 1)

The method of claim 1, comprising determining the frequency of TIGIT+KLRG1+CD8+ T-cells by flow cytometry.

### Claim 12 (depends on 1)

The method of claim 1, comprising determining a decrease in a percentage of CD8+ T-cells expressing proliferation markers Ki67 and/or CD57.

### Claim 13 (depends on 1)

The method of claim 1, comprising administering by intravenous infusion the 10 to 14 day course of teplizumab at a daily dose of 10-1000 micrograms/meter squared (μg/m2).

### Claim 14 (depends on 1)

The method of claim 1 comprising administering orally the 10 to 14 day course of teplizumab at a daily dose of 10-1000 micrograms/meter squared (μg/m2).

### Claim 15 (depends on 1)

The method of claim 1, comprising administering a daily dose of from about 5 to about 1200 μg/m2 of teplizumab over a 14 day course.

### Claim 16 (depends on 1)

The method of claim 1, comprising administering a 14 day course of teplizumab by IV infusion at about 51 μg/m2 on day 0, about 103 μg/m2 on day 1, about 207 μg/m2 on day 2, and about 413 μg/m2 on day 3, and one dose of about 826 μg/m2 on each of days 4 to 13.

### Claim 17 (depends on 1)

The method of claim 1, comprising determining the frequency of TIGIT+KLRG1+CD8+ T-cells in all the CD3+ T-cells in the non-diabetic subject prior to the administering step.

### Claim 18 (depends on 1)

The method of claim 1, comprising determining the frequency of TIGIT+KLRG1+CD8+ T-cells in all the CD3+ T-cells in the non-diabetic subject after the administering step.

### Claim 19 (depends on 1)

The method of claim 1, comprising determining, prior to or after said administering, the frequency of CD8+ T-cells that express CD127.

### Claim 20 (depends on 1)

The method of claim 1, wherein the frequency of TIGIT+KLRG1+CD8+Ki67+ T-cells is decreased by from 30% to 70%.

### Claim 21

A method of delaying the onset of clinical type 1 diabetes (T1D), comprising:
administering a prophylactically effective amount of teplizumab to a non-diabetic subject at risk for T1D, wherein the prophylactically effective amount of teplizumab comprises a 10 to 14 day course of teplizumab,
wherein at three months or more after the administration of the 10 to 14 day course of teplizumab, the subject has a frequency of about 5% to about 50% TIGIT+KLRG1+CD8+ T-cells in all CD3+ T-cells, indicative of successful delay of the onset of clinical T1D.

### Claim 22 (depends on 21)

The method of claim 21, comprising administering a first 10 to 14 day course of teplizumab and administering a second 10 to 14 day course of teplizumab,
wherein the administering of the second 10 to 14 day course of teplizumab is from 2 months to 36 months after the administering of the first course of teplizumab, and
wherein the administering of the second 10 to 14 day course of teplizumab increases the generation or maintenance of the TIGIT+KLRG1+CD8+ T-cells.

### Claim 23

A method of delaying the onset of clinical type 1 diabetes (T1D), comprising:
administering a prophylactically effective amount of teplizumab to a non-diabetic subject at risk for T1D, wherein the prophylactically effective amount comprises a 10 to 14 day course of teplizumab; and
measuring a frequency of TIGIT+KLRG1+CD8+ T-cells in all CD3+ T-cells in the non-diabetic subject at three months or more after the administration of the 10 to 14 day course of teplizumab,
wherein a measured frequency of about 5% to about 50% TIGIT+KLRG1+CD8+ T-cells in all CD3+ T-cells in the non-diabetic subject at three months or more after the administering of the 10 to 14 day course of teplizumab is indicative of successful delay of the onset of clinical T1D.