Antibodies for chelated radionuclides
AssigneeHoffmann-La Roche Inc.
InventorsChristian KLEIN, Pablo UMANA, Alexander HAAS, Barbara WEISER, Florian LIPSMEIER, Guy GEORGES, Sebastian FENN, Joerg MOELLEKEN, Felix BORMANN, Daniela MATSCHEKO
Life of this patent
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Abstract
The present application relates to antibodies which bind specifically to chelated radionuclides, including bispecific antibodies. It further relates to the use of such bispecific antibodies in applications such as radioimmunoimaging and radioimmunotherapy. It additionally relates to clearing agents and compositions useful in such methods.
Claims57
An antibody comprising an antigen binding site specific for DOTAM-lead (Pb) chelate, wherein said antigen binding site comprises at least:
- a) heavy chain CDR2 comprising the amino acid sequence FIGSRGDTYYASWAKG (SEQ ID NO:2), or a variant thereof having up to 1, 2, or 3 substitutions in SEQ ID NO:
- 2, wherein these substitutions do not include Phe50, Asp56 and Tyr58, and optionally also do not include Gly52 and/or Arg 54;
- b) heavy chain CDR3 comprising the amino acid sequence ERDPYGGGAYPPHL (SEQ ID NO:3), or a variant thereof having up to 1, 2, or 3 substitutions in SEQ ID NO:
- 3, wherein these substitutions do not include Glu95, Arg96, Asp97, Pro98, and optionally also do not include Ala100C, Tyr100D, and/or Pro100E and/or optionally also do not include Tyr99;
- c) light chain CDR1 comprising the amino acid sequence QSSHSVYSDNDLA (SEQ ID NO:4) or a variant thereof having up to 1, 2, or 3 substitutions in SEQ ID NO:
- 4, wherein these substitutions do not include Tyr28 and Asp32;
- d) light chain CDR3 comprising the amino acid sequence LGGYDDESDTYG (SEQ ID NO:6) or a variant thereof having up to 1, 2, or 3 substitutions in SEQ ID NO:
- 6, wherein these substitutions do not include Gly91, Tyr92, Asp93, Thr95c and Tyr96,
- wherein numbering is according to Kabat.
The antibody according any preceding claim, wherein the antigen binding site comprises at least one, two, three, four, five, or six CDRs selected from:
- a) heavy chain CDR1 comprising the amino acid sequence GFSLSTYSMS (SEQ ID NO:1)
- b) heavy chain CDR2 comprising the amino acid sequence FIGSRGDTYYASWAKWG (SEQ ID NO:2)
- c) heavy chain CDR3 comprising the amino acid sequence ERDPYGGGAYPPHL (SEQ ID NO:3).
- d) light chain CDR1 comprising the amino acid sequence QSSHSVYSDNDLA (SEQ ID NO:4)
- e) light chain CDR2 comprising the amino acid sequence QASKLAS (SEQ ID NO:
- 5)
- f) light chain CDR3 comprising the amino acid sequence LGGYDDESDTYG (SEQ ID NO:6).
An antibody according to any one of the preceding claims, which binds to the same epitope, or an overlapping epitope, of the Pb-DOTAM chelate as:
- i) an antibody having a heavy chain variable domain comprising an amino acid sequence of SEQ ID NO:
- 7 and a light chain variable domain comprising an amino acid sequence of SEQ ID NO:
- 8;
- or
- i) an antibody having a heavy chain variable domain comprising an amino acid sequence of SEQ ID NO:
- 9 and a light chain variable domain comprising an amino acid sequence of SEQ ID NO:
- 10.
The antibody according to any one of the preceding claims, which is human, chimeric or humanized.
An antibody according to any one of the preceding claims, wherein the antigen binding site comprises a heavy chain variable domain comprising an amino acid sequence selected from the group consisting of SEQ ID NO:
- 7 and SEQ ID NO 9, or a variant thereof comprising an amino acid sequence having at least 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% identity to SEQ ID NO:
- 7 or SEQ ID NO:
- 9.
An antibody according to any one of the preceding claims, wherein the antigen binding site comprises a light chain variable domain comprising an amino acid sequence selected from the group consisting of SEQ ID NO:
- 8 and SEQ ID NO:
- 10, or a variant thereof comprising an amino acid sequence having at least 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% identity to SEQ ID NO:
- 8 or 10.
An antibody according to any one of the preceding claims, wherein the antigen binding site comprises a heavy chain variable domain comprising an amino acid sequence of SEQ ID No. 7 and a light chain variable domain comprising an amino acid sequence of SEQ ID NO. 8.
An antibody according to any one of the preceding claims, wherein the antigen binding site comprises a heavy chain variable domain comprising an amino acid sequence of SEQ ID No. 9 and a light chain variable domain comprising an amino acid sequence of SEQ ID NO. 10.
An antibody according to any one of the preceding claims, wherein the antigen binding site binds to the Pb-DOTAM chelate with a Kd value of 100 pM, 50 pM, 20 pM, 10 pM, 5 pM, 1 pM or less.
An antibody according to any one of the preceding claims, wherein the antigen binding site binds to the Pb-DOTAM chelate and to a Bi-DOTAM chelate, and wherein the ratio of Kd values for the Bi-DOTAM chelate/Pb-DOTAM chelate is in the range of 0.1-10 or 1-10.
An antibody according to any one of the preceding claims, which is a whole antibody, or which is an antibody fragment selected from the group consisting of an Fv, Fab, Fab′, Fab′-SH, F(ab′)2, diabody, linear antibody, or single-chain antibody molecule.
An antibody according to any one of the preceding claims, wherein the antibody is coupled to a moiety which binds specifically to a target antigen.
The antibody according to claim 14 or 15, which is a multispecific or bispecific antibody, optionally a multispecific antibody or bispecific antibody according to any one of claims 17 to 51.
A multispecific or bispecific antibody comprising at least one antigen binding site specific for a Pb-DOTAM chelate and at least one antigen binding site for a target antigen.
The multispecific or bispecific antibody according to paragraph 30, wherein the antigen binding site specific for CD20 comprises a heavy chain variable domain comprising an amino acid sequence of SEQ ID NO:
- 45 and/or a light chain variable domain comprising an amino acid sequence of SEQ ID NO:
- 46.
An isolated polynucleotide or an isolated set of polynucleotides encoding an antibody according to any one of the preceding claims.
Dependencies are inferred from the claim text.