Novel TNFR2 Binding Molecules
AssigneeJulius-Maximilians-UniversitäT WüRzburg
InventorsHarald Wajant, Andreas Beilhack, Juliane Medler, Tim Steinfatt, Luc Van Rompaey
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Abstract
The present invention provides a binding molecule that specifically binds TNFR2, but not TNFR1. Preferably the binding molecule is an FcγR-independent agonist of TNFR2 and more preferably has a valency of at least two for binding TNFR2. The binding molecules have a variety of uses including diagnostic and therapeutic. The ability of the binding molecules to be able to modulate immune responses means that they are particularly suited for treating autoimmune diseases, or inflammatory conditions.
Claims31
A binding molecule that specifically binds TNFR2, but not TNFR1, where the binding molecule is an FcγR independent agonist of TNFR2 and has a valency of at least two for binding TNFR2.
The binding molecule of any one of the preceding claims, wherein at least one antigen-binding domain specific for TNFR2 of the binding molecule is a single domain binder (sdB) specific for TNFR2, preferably a single domain antibody (sdAb) specific for TNFR2.
The binding molecule of any one of the preceding claims, wherein the binding molecule comprises six TNFR2 specific antigen-binding sites that are each VHH antigen-binding domains specific for TNFR2.
The binding molecule of any one of the preceding claims, wherein:
- (a) the binding molecule comprises an antigen-binding site comprising a VHH domain comprising a set of three CDRs selected from the sets of SEQ ID NOs:
- 213/214/215;
- 216/217/218;
- 219/220/221;
- 222/223/224;
- 225/226/227;
- 228/229/230;
- 231/232/233;
- 234/235/236;
- 237/238/239;
- 240/241/242;
- 243/244/245;
- 246/247/248;
- 249/250/251;
- 252/253/254;
- or a variant set of CDRs of any of those sets with up to a total of five amino acid sequence changes, with the variant antigen-binding site retaining the ability to bind TNFR2;
- (b) the binding molecule comprises an antigen-binding site comprising a VHH domain comprising the three CDRs of SEQ ID NOs:
- 154/155/156 or a variant set of those three CDRs with up to a total of five amino acid sequence changes with the variant antigen-binding site retaining the ability to bind TNFR2;
- (c) the binding molecule comprises an antigen-binding site comprising a set of three CDRs selected from 154/155/156;
- 160/161/162;
- 163/164/165;
- 166/167/168;
- 169/170/171;
- 181/182/183;
- 187/188/189;
- 193/194/195 or a variant set of any thereof with up to five amino acid sequence changes with the antigen-binding site retaining the ability to bind TNFR2;
- (d) the binding molecule is hexavalent comprising six VHH antigen-binding sites which are all the same and are an antigen-binding site as defined in any of (a) to (c);
- (e) the binding molecule is hexavalent comprising two polypeptides, wherein each comprises three VHH antigen-binding sites, wherein all six antigen-binding sites are the same antigen-binding sites which is as defined in any of (a) to (c);
- (f) the binding molecule is hexavalent comprising six VHH antigen-binding sites, wherein at least two of the VHH antigen-binding sites have a different specificity for TNFR2, with at least one of those specificities conferred by a VHH antigen-binding site as defined in any of (a) to (c);
- (g) the binding molecule is hexavalent comprising six VHH antigen-binding sites, wherein at least three of the VHH antigen-binding sites have a different specificity for TNFR2, with at least one of those specificities conferred by a VHH antigen-binding site as defined in any of (a) to (c);
- or
- (h) the binding molecule is hexavalent comprising six VHH antigen-binding sites, wherein all six VHH antigen-binding sites have a different specificity for TNFR2, with at least one of those specificities conferred by a VHH antigen-binding site as defined in any of (a) to (c).
The binding molecule of any one of the preceding claims which is able to:
- (a) oligomerise TNFR2 on the surface of a cell expressing TNFR2, preferably to cluster six or more TNFR2 molecules on the cell surface;
- (b) trigger TNFR2 signalling;
- and/or
- (c) stimulate proliferation of leucocytes, preferably T cells, more preferably Treg cells.
A binding molecule that specifically binds TNFR2, but not TNFR1, where the binding molecule is an FcγR independent agonist of TNFR2, has a valency of at least two for binding TNFR2, and comprises polypeptides comprising mutant TNF-alpha that bind TNFR2, but not TNFR1, and an Fc region, or a tenascin peptide sequence, or both, that oligomerises the polypeptides,
- preferably wherein the binding molecule is one:
- (a) which does not comprise antibody sequences;
- (b) which comprises polypeptides comprising mutant TNF-alpha that binds TNFR2, but not TNFR1, and a tenascin peptide;
- (c) wherein the TNF-alpha mutants are TNF80;
- and/or
- (d) has a valency for TNFR2 of at least three, preferably having a valency for TNFR2 of six
The binding molecule of any one of the preceding claims for use as a medicament.
Dependencies are inferred from the claim text.