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US 12,715,923 B2Granted
Antibodies binding to GPRC5D
AssigneeHoffmann-La Roche Inc.
InventorsAlexander Bujotzek, Tony Christopeit, Tanja Fauti, Georg Fertig, Hélène Cécile Haegel, Christian Klein, Thomas Kraft, Stefan Lorenz, Maud Léa Mayoux, Anneliese Schneider
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Abstract
The present invention generally relates to antibodies that bind to GPRC5D, including bispecific antigen binding molecules e.g. for activating T cells. In addition, the present invention relates to polynucleotides encoding such antibodies, and vectors and host cells comprising such polynucleotides. The invention further relates to methods for producing the antibodies, and to methods of using them in the treatment of disease.
Claims39
A bispecific antigen binding molecule, comprising
- (a) a first antigen binding moiety that binds to a first antigen,
- wherein the first antigen is GPRC5D and the first antigen binding moiety comprises:
- (i) a heavy chain variable region (VH) comprising a heavy chain complementary determining region (HCDR) 1 comprising the amino acid sequence of SEQ ID NO:
- 83, a HCDR 2 comprising the amino acid sequence of SEQ ID NO:
- 84, and a HCDR 3 comprising the amino acid sequence of SEQ ID NO:
- 86, and a light chain variable region (VL) comprising a light chain complementarity determining region (LCDR) 1 comprising the amino acid sequence of SEQ ID NO:
- 87, a LCDR 2 comprising the amino acid sequence of SEQ ID NO:
- 88 and a LCDR 3 comprising the amino acid sequence of SEQ ID NO:
- 89;
- (ii) a heavy chain variable region (VH) comprising a heavy chain complementary determining region (HCDR) 1 comprising the amino acid sequence of SEQ ID NO:
- 83, a HCDR 2 comprising the amino acid sequence of SEQ ID NO:
- 85, and a HCDR 3 comprising the amino acid sequence of SEQ ID NO:
- 86, and a light chain variable region (VL) comprising a light chain complementarity determining region (LCDR) 1 comprising the amino acid sequence of SEQ ID NO:
- 87, a LCDR 2 comprising the amino acid sequence of SEQ ID NO:
- 88 and a LCDR 3 comprising the amino acid sequence of SEQ ID NO:
- 89;
- and
- (b) a second antigen binding moiety that binds to a second antigen wherein the second antigen is CD3 and the second antigen binding moiety comprises:
- a heavy chain variable region (VH) comprising a heavy chain complementary determining region (HCDR) 1 comprising the amino acid sequence of SEQ ID NO:
- 98, a HCDR 2 comprising the amino acid sequence of SEQ ID NO:
- 99, and a HCDR 3 comprising the amino acid sequence of SEQ ID NO:
- 100, and a light chain variable region (VL) comprising a light chain complementarity determining region (LCDR) 1 comprising the amino acid sequence of SEQ ID NO:
- 101, a LCDR 2 comprising the amino acid sequence of SEQ ID NO:
- 102 and a LCDR 3 comprising the amino acid sequence of SEQ ID NO:
- 103.
22 more elements
A bispecific antigen binding molecule comprising a polypeptide comprising the amino acid sequence of SEQ ID NO:
- 122, a polypeptide comprising the amino acid sequence of SEQ ID NO:
- 123, a polypeptide comprising the amino acid sequence of SEQ ID NO:
- 124 and a polypeptide comprising the amino acid sequence of SEQ ID NO:
- 125.
1 more element
A bispecific antigen binding molecule, comprising:
- (a) a first Fab that binds to GPRC5D comprising a VH comprising a HCDR 1 comprising the amino acid sequence of SEQ ID NO:
- 83, a HCDR 2 comprising the amino acid sequence of SEQ ID NO:
- 85, and a HCDR 3 comprising the amino acid sequence of SEQ ID NO:
- 86, and a VL comprising a LCDR 1 comprising the amino acid sequence of SEQ ID NO:
- 87, a LCDR 2 comprising the amino acid sequence of SEQ ID NO:
- 88 and a LCDR 3 comprising the amino acid sequence of SEQ ID NO:
- 89;
- (b) a second Fab that binds to CD3 comprising a VH comprising a HCDR 1 comprising the amino acid sequence of SEQ ID NO:
- 98, a HCDR 2 comprising the amino acid sequence of SEQ ID NO:
- 99, and a HCDR 3 comprising the amino acid sequence of SEQ ID NO:
- 100, and a VL comprising a LCDR 1 comprising the amino acid sequence of SEQ ID NO:
- 101, a LCDR 2 comprising the amino acid sequence of SEQ ID NO:
- 102 and a LCDR 3 comprising the amino acid sequence of SEQ ID NO:
- 103;
- and
- (c) a third Fab identical to the first Fab, and
- wherein the bispecific antigen binding molecule comprises an IgG1 Fc domain composed of a first and a second subunit.
14 more elements
A bispecific antigen binding molecule, comprising:
- (a) a first Fab that binds to GPRC5D comprising a VH comprising a HCDR 1 comprising the amino acid sequence of SEQ ID NO:
- 83, a HCDR 2 comprising the amino acid sequence of SEQ ID NO:
- 85, and a HCDR 3 comprising the amino acid sequence of SEQ ID NO:
- 86, and a VL comprising a LCDR 1 comprising the amino acid sequence of SEQ ID NO:
- 87, a LCDR 2 comprising the amino acid sequence of SEQ ID NO:
- 88 and a LCDR 3 comprising the amino acid sequence of SEQ ID NO:
- 89;
- (b) a second Fab that binds to CD3 comprising a VH comprising a HCDR 1 comprising the amino acid sequence of SEQ ID NO:
- 98, a HCDR 2 comprising the amino acid sequence of SEQ ID NO:
- 99, and a HCDR 3 comprising the amino acid sequence of SEQ ID NO:
- 100, and a VL comprising a LCDR 1 comprising the amino acid sequence of SEQ ID NO:
- 101, a LCDR 2 comprising the amino acid sequence of SEQ ID NO:
- 102 and a LCDR 3 comprising the amino acid sequence of SEQ ID NO:
- 103, wherein in the second Fab, the variable domains VL and VH of the Fab light chain and the Fab heavy chain are replaced by each other;
- and
- (c) a third Fab identical to the first Fab, and
- wherein the bispecific antigen binding molecule comprises an IgG1 Fc domain composed of a first and a second subunit, wherein the first Fab is fused at the C-terminus of the Fab heavy chain to the N-terminus of the Fab heavy chain of the second Fab;
- the second Fab is fused at the C-terminus of the Fab heavy chain to the N-terminus of the first subunit of the Fc domain;
- and the third Fab is fused at the C-terminus of the Fab heavy chain to the N-terminus of the second subunit of the Fc domain.
16 more elements
A bispecific antigen binding molecule, comprising:
- (a) a first Fab that binds to GPRC5D comprising a VH comprising a HCDR 1 comprising the amino acid sequence of SEQ ID NO:
- 83, a HCDR 2 comprising the amino acid sequence of SEQ ID NO:
- 85, and a HCDR 3 comprising the amino acid sequence of SEQ ID NO:
- 86, and a VL comprising a LCDR 1 comprising the amino acid sequence of SEQ ID NO:
- 87, a LCDR 2 comprising the amino acid sequence of SEQ ID NO:
- 88 and a LCDR 3 comprising the amino acid sequence of SEQ ID NO:
- 89;
- (b) a second Fab that binds to CD3 comprising a VH comprising a HCDR 1 comprising the amino acid sequence of SEQ ID NO:
- 98, a HCDR 2 comprising the amino acid sequence of SEQ ID NO:
- 99, and a HCDR 3 comprising the amino acid sequence of SEQ ID NO:
- 100, and a VL comprising a LCDR 1 comprising the amino acid sequence of SEQ ID NO:
- 101, a LCDR 2 comprising the amino acid sequence of SEQ ID NO:
- 102 and a LCDR 3 comprising the amino acid sequence of SEQ ID NO:
- 103, wherein in the second Fab, the variable domains VL and VH of the Fab light chain and the Fab heavy chain are replaced by each other;
- and
- (c) a third Fab identical to the first Fab,
- wherein in the constant domain CL of the first Fab the amino acid at position 124 is substituted by lysine (K) (numbering according to Kabat) and the amino acid at position 123 is substituted by arginine (R) (numbering according to Kabat), and in the constant domain CH1 of the first Fab the amino acid at position 147 is substituted by glutamic acid (E) (numbering according to Kabat EU index) and the amino acid at position 213 is substituted by glutamic acid (E) (numbering according to Kabat EU index), and
- wherein the bispecific antigen binding molecule comprises an IgG1 Fc domain composed of a first and a second subunit, wherein:
- (i) the first Fab is fused at the C-terminus of the Fab heavy chain to the N-terminus of the Fab heavy chain of the second Fab via a peptide linker;
- the second Fab is fused at the C-terminus of the Fab heavy chain to the N-terminus of the first subunit of the Fc domain;
- and the third Fab is fused at the C-terminus of the Fab heavy chain to the N-terminus of the second subunit of the Fc domain;
- (ii) in the first subunit of the Fc domain the threonine residue at position 366 is replaced with a tryptophan residue (T366W), and in the second subunit of the Fc domain the tyrosine residue at position 407 is replaced with a valine residue (Y407V);
- the threonine residue at position 366 is replaced with a serine residue (T366S);
- and the leucine residue at position 368 is replaced with an alanine residue (L368A) (numberings according to Kabat EU index);
- (iii) in the first subunit of the Fc domain the serine residue at position 354 is replaced with a cysteine residue (S354C) and in the second subunit of the Fc domain additionally the tyrosine residue at position 349 is replaced by a cysteine residue (Y349C) (numberings according to Kabat EU index);
- and
- (iv) in each of the first and the second subunit of the Fc domain the leucine residue at position 234 is replaced with an alanine residue (L234A), the leucine residue at position 235 is replaced with an alanine residue (L235A) and the proline residue at position 329 is replaced by a glycine residue (P329G) (numbering according to Kabat EU index).
24 more elements
Dependencies are inferred from the claim text.