Methods for administering therapeutic doses of bispecific t-cell engaging molecules for the treatment of cancer

Patent metadata

Field	Value
Publication number	US-2023398147-A1
Application number	US-202118026505-A
Country	US
Kind code	A1
Filing date	Sep 15, 2021
Priority date	Sep 16, 2020
Publication date	Dec 14, 2023
Grant date	—

Abstract

The present invention relates to methods for administering therapeutic doses of bispecific T-cell engaging molecules for the treatment of cancer in a patient. The administration methods reduce the incidence and/or severity of adverse events, such as cytokine release syndrome, and entail administering to a patient a priming dose of the bispecific T-cell engaging molecule by continuous intravenous infusion over a period of days followed by administration of a therapeutic dose of the bispecific T-cell engaging molecule by a bolus intravenous infusion at dosing intervals of at least a week.

First claim

What is claimed:

1 . A method for administering a therapeutic dose of a bispecific T-cell engaging molecule to a patient diagnosed with cancer, comprising administering to the patient an initiation cycle of the bispecific T-cell engaging molecule, said initiation cycle comprising:
administering a priming dose of the bispecific T-cell engaging molecule by continuous intravenous infusion over a period of 1 day to 7 days; and administering after the priming dose a therapeutic dose of the bispecific T-cell engaging molecule by a bolus intravenous infusion, wherein the bispecific T-cell engaging molecule comprises a first domain that specifically binds to a target cancer cell antigen, a second domain that specifically binds to human CD3, and an Fc domain.

2 . The method of claim 1 , wherein the therapeutic dose of the bispecific T-cell engaging molecule is administered once every 7 days for the duration of the initiation cycle.

3 . The method of claim 1 , wherein the therapeutic dose of the bispecific T-cell engaging molecule is administered once every 14 days for the duration of the initiation cycle.

4 . The method of any one of claims 1 to 3 , wherein the priming dose of the bispecific T-cell engaging molecule is administered over a period of about 2 days.

5 . The method of any one of claims 1 to 3 , wherein the priming dose of the bispecific T-cell engaging molecule is administered over a period of about 3 days.

6 . The method of any one of claims 1 to 3 , wherein the priming dose of the bispecific T-cell engaging molecule is administered over a period of about 4 days.

7 . The method of any one of claims 1 to 3 , wherein the priming dose of the bispecific T-cell engaging molecule is administered over a period of about 5 days.

8 . The method of any one of claims 1 to 3 , wherein the priming dose of the bispecific T-cell engaging molecule is administered over a period of about 7 days.

9 . The method of any one of claims 1 to 8 , wherein the therapeutic dose is administered on the same day the continuous intravenous infusion of the priming dose ends.

10 . The method of any one of claims 1 to 8 , wherein the therapeutic dose is administered about 1 day to about 7 days after the priming dose.

11 . The method of claim 10 , wherein the therapeutic dose is administered about 1 day after the priming dose.

12 . The method of claim 10 , wherein the therapeutic dose is administered about 3 days after the priming dose.

13 . The method of claim 10 , wherein the therapeutic dose is administered about 4 days after the priming dose.

14 . The method of claim 10 , wherein the therapeutic dose is administered about 5 days after the priming dose.

15 . The method of claim 10 , wherein the therapeutic dose is administered about 6 days after the priming dose.

16 . The method of any one of claims 1 to 15 , further comprising administering a boost dose of the bispecific T-cell engaging molecule by a bolus intravenous infusion after the priming dose and before the therapeutic dose.

17 . The method of claim 16 , wherein the boost dose is about 30% to about 40% of the priming dose.

18 . The method of any one of claims 1 to 17 , wherein the duration of the initiation cycle is about 28 days.

19 . The method of claim 18 , wherein the priming dose of the bispecific T-cell engaging molecule is administered over days 1 to 3 of the initiation cycle and the therapeutic dose of the bispecific T-cell engaging molecule is administered on days 8 and 22 of the initiation cycle.

20 . The method of claim 18 , wherein the priming dose of the bispecific T-cell engaging molecule is administered over days 1 to 2 of the initiation cycle and the therapeutic dose of the bispecific T-cell engaging molecule is administered on days 8, 15, and 22 of the initiation cycle.

21 . The method of claim 20 , further comprising administering a boost dose of the bispecific T-cell engaging molecule by bolus intravenous infusion on day 3 of the initiation cycle.

22 . The method of claim 18 , wherein the priming dose of the bispecific T-cell engaging molecule is administered over days 1 to 7 of the initiation cycle and the therapeutic dose of the bispecific T-cell engaging molecule is administered on days 8, 15, and 22 of the initiation cycle.

23 . The method of claim 18 , wherein the priming dose of the bispecific T-cell engaging molecule is administered over days 1 to 4 of the initiation cycle and the therapeutic dose of the bispecific T-cell engaging molecule is administered on days 8, 15, and 22 of the initiation cycle.

24 . The method of any one of claims 1 to 23 , wherein the priming dose is about 10% to about 80% of the therapeutic dose.

25 . The method of any one of claims 1 to 23 , wherein the priming dose is about 15% to about 50% of the therapeutic dose.

26 . The method of any one of claims 1 to 25 , further comprising administering to the patient a maintenance cycle of the bispecific T-cell engaging molecule, wherein the maintenance cycle comprises administering the therapeutic dose of the bispecific T-cell engaging molecule by a bolus intravenous infusion once every 7 days or once every 14 days.

27 . The method of claim 26 , wherein the duration of the maintenance cycle is about 28 days.

28 . The method of claim 26 or 27 , wherein the maintenance cycle is administered the following day after completing the initiation cycle.

29 . The method of claim 26 or 27 , wherein the maintenance cycle is administered about 7 days following completion of the initiation cycle.

30 . The method of any one of claims 26 to 29 , wherein two or more maintenance cycles are administered to the patient.

31 . The method of any one of claims 1 to 30 , wherein the first domain of the bispecific T-cell engaging molecule specifically binds to a target cancer cell antigen selected from MUC17, CLDN18.2, CD19, CD33, FLT3, DLL3, BCMA and PSMA.

32 . The method of any one of claims 1 to 31 , wherein the bispecific T-cell engaging molecule comprises, in an amino to carboxyl order:
(i) the first domain that specifically binds to the target cancer cell antigen comprising a first immunoglobulin heavy chain variable region (VH1) and a first immunoglobulin light chain variable region (VL1);
(ii) the second domain that specifically binds to human CD3 comprising a second immunoglobulin heavy chain variable region (VH2), and a second immunoglobulin light chain variable region (VL2); and
(iii) the Fc domain comprising two Fc monomers, each monomer comprising an immunoglobulin hinge region, a CH2 domain, and a CH3 domain, wherein said two monomers are fused to each other via a peptide linker.

33 . The method of claim 31 or 32 , wherein the first domain of the bispecific T-cell engaging molecule specifically binds to PSMA and the patient is diagnosed with prostate cancer.

34 . The method of claim 33 , wherein the first domain comprises a VH1 comprising a CDRH1 having the sequence of SEQ ID NO: 51, a CDRH2 having the sequence of SEQ ID NO: 52, and a CDRH3 having the sequence of SEQ ID NO: 53, and a VL1 comprising a CDRL1 having the sequence of SEQ ID NO: 55, a CDRL2 having the sequence of SEQ ID NO: 56, and a CDRL3 having the sequence of SEQ

Assignees

• Amgen Inc
• Amgen Res Munich Gmbh

Inventors

• Mccullough Adam B
• Kouros-Mehr Hosein
• Kufer Peter
• Salvati Mark
• Minella Alexander C
• Nagorsen Dirk
• Upreti Vijay
• Minocha Mukul
• Houk Brett

Classifications

• A61K40/11

  T-cells, e.g. tumour infiltrating lymphocytes [TIL] or regulatory T [Treg] cells; Lymphokine-activated killer [LAK] cells · CPC title

• A61K35/17 Primary

  Lymphocytes; B-cells; T-cells; Natural killer cells; Interferon-activated or cytokine-activated lymphocytes (when activated by a specific antigen A61K39/00) · CPC title

• C07K16/2809 Primary

  against the T-cell receptor (TcR)-CD3 complex · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• C07K14/8103

  Exopeptidase (E.C. 3.4.11-19) inhibitors · CPC title