Bispecific antibody against ox40 and ctla-4
OwnerPeter Ellmark, Christina Furebring +2inventors
InventorsPeter Ellmark, Christina Furebring, Per Norlen, Niina Veitonmaki
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Abstract
The present invention provides bispecific polypeptides, such as bispecific antibodies, comprising a first binding domain capable of specifically binding to OX40, and a second binding domain capable of specifically binding to CTLA-4. The invention further provides compositions of said bispecific polypeptides, as well as methods and uses of the same.
Claims46
A bispecific polypeptide comprising a first binding domain, designated B1, which is capable of specifically binding to OX40, and a second binding domain, designated B2, which is capable of specifically binding to CTLA-4.
A polypeptide according to any one of the preceding claims wherein the polypeptide is a bispecific antibody.
A polypeptide according to any one of the preceding claims wherein the bispecific polypeptide is selected from the groups consisting of:
- (a) bivalent bispecific antibodies, such as IgG-scFv bispecific antibodies (for example, wherein B1 is an intact IgG and B2 is an scFv attached to B1 at the N-terminus of a light chain and/or at the C-terminus of a light chain and/or at the N-terminus of a heavy chain and/or at the C-terminus of a heavy chain of the IgG, or vice versa);
- (b) monovalent bispecific antibodies, such as a DuoBody® or a ‘knob-in-hole’ bispecific antibody (for example, an scFv-KIH, scFv-KIHr, a BiTE-KIH or a BiTE-KIHr;
- (c) scFv2-Fc bispecific antibodies (for example, ADAPTIR™ bispecific antibodies);
- (d) BiTE/scFv2 bispecific antibodies;
- (e) DVD-Ig bispecific antibodies or other IgG-FAb, FAb-IgG bispecific antibodies regardless of bivalency or linkers/connectors employed;
- (f) DART-based bispecific antibodies (for example, DART-Fc, DART2-Fc or DART);
- (g) DNL-Fab3 bispecific antibodies;
- and
- (h) scFv-HSA-scFv bispecific antibodies.
A polypeptide according to any one of the preceding claims comprising a human Fc region or a variant of a said region, where the region is an IgG1, IgG2, IgG3 or IgG4 region, preferably an IgG1 or IgG4 region.
A polypeptide according to any of the preceding claims, wherein the polypeptide is capable of inducing antibody dependent cell cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), complement-dependent cytotoxicity (CDC), and/or apoptosis.
A polypeptide according to any one of the preceding claims, wherein:
- B1 is an antibody, or antigen binding fragment thereof, specific for OX40;
- and
- B2 is a polypeptide binding domain specific for CTLA-4, which comprises or consists of:
- i) the amino acid sequence of SEQ ID NO:
- 3;
- or
- ii) an amino acid sequence in which at least one amino acid is changed when compared to the amino acid sequence of SEQ ID NO:
- 3 provided that said binding domain binds to human CTLA-4 with higher affinity than wild-type human CD86.
A polypeptide according to any one of the preceding claims in which the CTLA-4 specifically bound by the polypeptide is primate or murine, preferably human, CTLA-4, and/or wherein the OX40 specifically bound by the polypeptide is primate, preferably human, OX40.
A polypeptide according to any one of the preceding claims in which B1 comprises at least one heavy chain (H) and/or at least one light chain (L) and B2 is attached to said at least one heavy chain (H) or least one light chain (L).
A polypeptide according to any one of the preceding claims which comprises or consists of a polypeptide chain arranged according to any one of the following formulae, written in the direction N-C:
- L-(X)n-B2;
- (A)
- B2-(X)n-L;
- (B)
- B2-(X)n-H;
- (C)
- H—(X)n-B2;
- (D)
- wherein X is a linker and n is 0 or 1.
A polypeptide according to any one of the preceding claims, which binds to human OX40 with a Kd of less than 50×10−10M, 25×10−10M, or 20×10−10M and/or which binds to human CTLA-4 with a Kd value which is less than 60×10−9M, 25×10−9M, or 10×10−9M.
A polypeptide according to any one of the preceding claims, which induces an increase in the activity of an effector T cell, preferably a CD4+ effector T cell, optionally wherein said increase is at least 1.5 fold, 4.5 fold or 7 fold higher than the increase in activity of an effector T cell induced by a combination of B1 and B2 administered to the T cell as separate molecules.
A polypeptide according to any one of the preceding claims which competes for binding to OX40 with antibody 1166/1167;
- and/or which competes for binding to CTLA-4 with CD86 mutant 1040 (SEQ ID NO:
- 17).
A polypeptide according to any one of the preceding claims which competes for binding to OX40 with antibody 1166/1261, and/or which competes for binding to CTLA-4 with antibody 1166/1261.
A polypeptide according to any one of the preceding claims, wherein 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acids in said amino acid sequence of B2 (ii) are substituted when compared to the amino acid sequence of SEQ ID NO:
- 3;
- optionally wherein there are no insertions or deletions compared to the amino acid sequence of SEQ ID NO:
- 3.
A polypeptide according to any one of the preceding claims wherein said amino acid sequence of B2 comprises or consists of an amino acid sequence selected from any one of SEQ ID NOs 6 to 24 (as shown in Table C), or variants of said sequences which have more than 60%, or more than 70%, e.g. 75 or 80%, preferably more than 85%, e.g. more than 90 or 95% amino acid identity to the amino acid sequences of SEQ ID NOs 6 to 24.
A polypeptide according to any one of the preceding claims wherein said amino acid sequence of B2 comprises or consists of the amino acid sequence of SEQ ID NO:
- 17 (CD86 mutant 1040, as shown in Table C).
A polypeptide according to any one of the preceding claims, wherein B1 exhibits at least one of the following functional characteristics when present independently of B2:
- I. binding to human OX40 with a KD value which is less than 10×10−10M, more preferably less than 5×10−10M;
- II. does not bind to murine OX40;
- and
- III. does not bind to other human TNFR superfamily members, for example human CD137 or CD40
A polypeptide according to any one of the preceding claims, wherein B1 comprises any one, two, three, four, five or all six features independently selected from the following:
- (a) a heavy chain CDR1 sequence which is 8 amino acids in length and comprises the consensus sequence:
- “G, F, T, F, G/Y/S, G/Y/S, Y/S, Y/S/A”;
- (b) a heavy chain CDR2 sequence which is 8 amino acids in length and comprises the consensus sequence:
- “I, G/Y/S/T, G/S/Y, S/Y, G/S/Y, G/S/Y, G/S/Y, T”;
- (c) a heavy chain CDR3 sequence which is 9 to 17 amino acids in length and which comprises the consensus sequence of:
- “A, R, G/Y/S/H, G/Y/F/V/D, G/Y/P/F, −/H/S, −/N/D/H, −/Y/G, −/Y, −/Y, −/W/A/V, −/A/Y, −/D/A/Y/G/H/N, Y/S/W/A/T, L/M/I/F, D, Y”
- (d) a light chain CDR1 sequence which consists of the sequence:
- “Q, S, I, S, S, Y”;
- (e) a light chain CDR2 sequence which consists of the sequence:
- “A, A, S”;
- (f) a light chain CDR3 sequence which is 8 to 10 amino acids in length and comprises the consensus sequence:
- “Q,Q, S/Y/G, −/Y/H/G, −/S/Y/G/D/W, S/Y/G/D, S/Y/G/T, P/L, Y/S/H/L/F, T”;
- wherein the heavy chain CDR3 sequence of (c) is preferably a sequence of 10 amino acids in length which comprises the consensus sequence “A, R, Y/H, D, Y, A/Y/G, S/W/A, M/L, D, Y”;
- and
- the light chain CDR3 sequence of (f) preferably consists of the sequence “Q, Q, Y, Y, W, Y, G, L, S, T”.
A polypeptide according to any one of the preceding claims, wherein B1 comprises all three heavy chain CDR sequences of a VH sequence as shown in Table A(1) and/or all three light chain CDR sequences of a VL sequence as shown in Table A(2) or wherein B1 comprises a heavy chain VH sequence and/or a light chain VL sequence as shown in Table B.
A polypeptide according to any one of the preceding claims, wherein B1 comprises a heavy chain CDR3 sequence of 11 amino acids in length which comprises the consensus sequence “A, R, Y/H, D, Y, A/Y/G, S/W/A, M/L, D, Y” and the light chain VL sequence of SEQ ID NO:
- 89 (1167 as shown in Table B), optionally wherein the light chain VL sequence of SEQ ID NO:
- 89 is present as part of the longer sequence of SEQ ID NO:
- 125 (1261 as shown in Table D).
A polypeptide according to any one of the preceding claims, wherein binding domain B1 comprises the light chain VL sequence of SEQ ID NO:
- 89 (1167 as shown in Table B), and the heavy chain VH sequence of SEQ ID NO:
- 91 (1166 as shown in Table B), or variants of said sequences which have more than 60%, or more than 70%, e.g. 75 or 80%, preferably more than 85%, e.g. more than 90 or 95% amino acid identity to SEQ ID NO:
- 89 and/or SEQ ID NO:
- 91.
A polypeptide according to any one of the preceding claims, wherein B1 comprises an human Fc region or a variant of a said region, where the region is an IgG1, IgG2, IgG3 or IgG4 region, preferably an IgG1 or IgG4 region.
A polypeptide according to any one of the preceding claims, which comprises or consists of the amino acid sequence of any one of SEQ ID NOs 125 to 134, optionally wherein said polypeptide is a provided as a component part of an antibody, or variants of said sequences which have more than 60%, or more than 70%, e.g. 75 or 80%, preferably more than 85%, e.g. more than 90 or 95% amino acid identity to the amino acid sequences of SEQ ID NOs 125 to 134.
A polypeptide according to any one of the preceding claims, which comprises or consists of the amino acid sequence of SEQ ID NO 125 (1261 as shown in Table D).
A polypeptide according to any one of the preceding claims, which comprises or consists of the amino acid sequence of SEQ ID NO 125 and/or the amino acid sequence of SEQ ID NO:
- 91, or variants of said sequences which have more than 60%, or more than 70%, e.g. 75 or 80%, preferably more than 85%, e.g. more than 90 or 95% amino acid identity to SEQ ID NO:
- 125 and/or SEQ ID NO:
- 91.
A polypeptide according to any one of the preceding claims, which comprises or consists of an amino acid sequence of SEQ ID NO:
- 125 (1261 as shown in Table D). and an amino acid sequence of SEQ ID NO:
- 91 (1161, as shown in Table B).
A polypeptide according to any one of the preceding claims, wherein the bispecific polypeptide is capable of inducing a synergistic increase in the intratumoural CD8/Treg ration compared to the combined effect of the individual monospecific counterpart polypeptides.
A bispecific polypeptide according to any one of the preceding claims for use as a medicament.
A method of treating or preventing a disease or condition in an individual, the method comprising administering to an individual a bispecific polypeptide according to any one of the preceding claims.
Dependencies are inferred from the claim text.