US 11,306,154 B2Granted

Methods of treating cancer by administering antigen-binding molecules comprising a TNF family ligand trimer

AssigneeHoffmann-La Roche Inc.

InventorsMaria Amann, Peter Bruenker, Christina Claus, Claudia Ferrara Koller, Sandra Grau-Richards, Christian Klein, Viktor Levitski, Ekkehard Moessner, Joerg Thomas Regula, Pablo Umana

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Abstract

The invention relates to novel TNF family ligand trimer-containing antigen binding molecules comprising (a) at least one moiety capable of specific binding to a target cell antigen and (b) a first and a second polypeptide that are linked to each other by a disulfide bond, characterized in that the first polypeptide comprises two ectodomains of a TNF ligand family member or fragments thereof that are connected to each other by a peptide linker and in that the second polypeptide comprises only one ectodomain of said TNF ligand family member or a fragment thereof.

Claims56

Dependent claims

A method of treating a cancer in an individual, the method comprising administering to said individual a therapeutically effective amount of a composition comprising a TNF family ligand trimer-containing antigen-binding molecule, said molecule comprising:

(a) at least one antigen-binding domain comprising a light chain variable region (VL) and a heavy chain variable region (VH) capable of specific binding to a target cell antigen, wherein the target cell antigen is Fibroblast Activation Protein (FAP),
(b) a first polypeptide and a second polypeptide that are linked to each other by a disulfide bond, wherein the first polypeptide comprises two ectodomains of a TNF family ligand, or fragments thereof, that are connected to each other by a peptide linker and the second polypeptide comprises only one ectodomain of the TNF family ligand, or fragment thereof,
wherein the ectodomain of the TNF family ligand, or fragment thereof, comprises the amino acid sequence selected from the group consisting of SEQ ID NO:1, SEQ ID NO:
2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:96, SEQ ID NO:
373, SEQ ID NO:374, and SEQ ID NO:375, and
(c) an Fc domain composed of a first subunit and a second subunit, wherein the first subunit and the second subunit are capable of stable association with each other,
wherein the TNF family ligand is 4-1BBL, and wherein the composition comprising the TNF family ligand trimer-containing antigen-binding molecule is in a pharmaceutically acceptable form.

4 more elements

(a) a first heavy chain and a first light chain, wherein the first heavy chain and the first light chain taken together comprise a Fab molecule capable of specific binding to a target cell antigen, wherein the target cell antigen is Fibroblast Activation Protein (FAP), and a first polypeptide comprising two ectodomains of a TNF family ligand or fragments thereof connected to each other by a first peptide linker and fused at its C-terminus by a second peptide linker to a second heavy chain, and a second polypeptide comprising only one ectodomain of the TNF family ligand or fragment thereof fused at its C-terminus by a third peptide linker to a second light chain, wherein the TNF family ligand is 4-1BBL, or
(b) a first heavy chain and a first light chain, wherein the first heavy chain and the first light chain taken together comprise a Fab molecule capable of specific binding to a target cell antigen, wherein the target cell antigen is FAP, and a first polypeptide comprising two ectodomains of a TNF family ligand or fragments thereof connected to each other by a first peptide linker and fused at its C-terminus by a second peptide linker to a second light chain, and a second polypeptide comprising only one ectodomain of the TNF family ligand or fragment thereof fused at its C-terminus by a third peptide linker to a second heavy chain, wherein the TNF family ligand is 4-1BBL,
wherein the ectodomain of the TNF family ligand, or fragment thereof, comprises the amino acid sequence selected from the group consisting of SEQ ID NO:1, SEQ ID NO:
2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:96, SEQ ID NO:
373, SEQ ID NO:374, and SEQ ID NO:375,
wherein the composition comprising the TNF family ligand trimer-containing antigen-binding molecule is in a pharmaceutically acceptable form.

3 more elements

(a) an antigen-binding domain capable of specific binding to Fibroblast Activation Protein (FAP), comprising a heavy chain variable region (VH) comprising (i) CDR-H1 comprising the amino acid sequence of SEQ ID NO:100, (ii) CDR-H2 comprising the amino acid sequence of SEQ ID NO:101, and (iii) CDR-H3 comprising the amino acid sequence of SEQ ID NO:102, and a light chain variable region (VL) comprising (iv) CDR-L1 comprising the amino acid sequence of SEQ ID NO:103, (v) CDR-L2 comprising the amino acid sequence of SEQ ID NO:104, and (vi) CDR-L3 comprising the amino acid sequence of SEQ ID NO:105;
(b) a first polypeptide and a second polypeptide that are linked to each other by a disulfide bond, wherein the first polypeptide comprises the amino acid sequence of SEQ ID NO:97, and the second polypeptide comprises the amino acid sequence of SEQ ID NO:96, and
(c) an Fc domain composed of a first subunit and a second subunit, wherein the first subunit and the second subunit are capable of stable association with each other,
wherein the composition comprising the TNF family ligand trimer-containing antigen-binding molecule is in a pharmaceutically acceptable form.

1 more element

(a) an antigen-binding domain capable of specific binding to Fibroblast Activation Protein (FAP) comprising a first heavy chain comprising a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO:106, and a first light chain comprising a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO:107,
(b) a second heavy chain comprising the amino acid sequence of SEQ ID NO:97,
(c) a second light chain comprising the amino acid sequence of SEQ ID NO:96, and
(d) an Fc domain composed of a first subunit and a second subunit, wherein the first subunit and the second subunit are capable of stable association with each other,
wherein the composition comprising the TNF family ligand trimer-containing antigen-binding molecule is in a pharmaceutically acceptable form.

2 more elements

(a) an antigen-binding domain capable of specific binding to Fibroblast Activation Protein (FAP) comprising a first heavy chain comprising a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO:106, and a first light chain comprising a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO:107,
(b) a second heavy chain comprising the amino acid sequence of SEQ ID NO:119,
(c) a second light chain comprising the amino acid sequence of SEQ ID NO:120, and
(d) an Fc domain composed of a first subunit and a second subunit, wherein the first subunit and the second subunit are capable of stable association with each other,
wherein the composition comprising the TNF family ligand trimer-containing antigen-binding molecule is in a pharmaceutically acceptable form.

2 more elements

(a) a first heavy chain comprising the amino acid sequence of SEQ ID NO:164, a first light chain comprising the amino acid sequence of SEQ ID NO:125, a second heavy chain comprising the amino acid sequence of SEQ ID NO:115, and a second light chain comprising the amino acid sequence of SEQ ID NO:116;
(b) a first heavy chain comprising the amino acid sequence of SEQ ID NO:164, a first light chain comprising the amino acid sequence of SEQ ID NO:125, a second heavy chain comprising the amino acid sequence of SEQ ID NO:117, and a second light chain comprising the amino acid sequence of SEQ ID NO:118;
(c) two light chains each comprising the amino acid sequence of SEQ ID NO:125, a first heavy chain comprising the amino acid sequence of SEQ ID NO:123, and a second heavy chain comprising the amino acid sequence of SEQ ID NO:124;
(d) a first heavy chain comprising the amino acid sequence of SEQ ID NO:164, a first light chain comprising the amino acid sequence of SEQ ID NO:125, a second heavy chain comprising the amino acid sequence of SEQ ID NO:119, and a second light chain comprising the amino acid sequence of SEQ ID NO:120;
(e) a first heavy chain comprising the amino acid sequence of SEQ ID NO:164, a first light chain comprising the amino acid sequence of SEQ ID NO:125, a second heavy chain comprising the amino acid sequence of SEQ ID NO:173, and a second light chain comprising the amino acid sequence of SEQ ID NO:174;
or
(f) two light chains each comprising the amino acid sequence of SEQ ID NO:125, a first heavy chain comprising the amino acid sequence of SEQ ID NO:126, and a second heavy chain comprising the amino acid sequence of SEQ ID NO:127,
wherein the composition comprising the TNF family ligand trimer-containing antigen-binding molecule is in a pharmaceutically acceptable form.

5 more elements

Dependencies are inferred from the claim text.

Facts

Application: 16/522,391Filed 25 Jul 2019 · division
Priority: EP 1419326014 Nov 2014
Published: US 2020/0247904 A16 Aug 2020
Granted: 19 Apr 2022
Term ends: Not estimatedThe source records don’t support an estimate.

Classification25 codes

C07K 16/40
Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies: against enzymes
A61K 39/395
Medicinal preparations containing antigens or antibodies: antibodies ; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
A61K 47/6849
The modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site: the antibody targeting a receptor, a cell…
A61P 35/00
Antineoplastic agents

Family

PCT/EP2015/076528Parent of this continuation · filed 13 Nov 2015
Application15/067,024Parent of this division · filed 10 Mar 2016
US 2020/0247904 A1Pre-grant publication · published 6 Aug 2020
US 10,392,445 B2Parent of this division
Application15/067,024Parent of this continuation
US 2016/0200833 A1Published application
US 11,306,154 B2This patent

From the US filing history. Foreign family members aren’t listed.

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