In vivo imaging of an als biomarker and means therefor
AssigneeAL-S Pharma AG
InventorsBrigitte GUÉRIN, Sébastien TREMBLAY, Samia AIT-MOHAND, Michael SALZMANN, Marcel MAIER
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Abstract
Provided are labeled antibody conjugates for use in a method of diagnosing ALS or monitoring drug therapy and/or progression of ALS by in vivo detecting and tracing misfolded SOD1 by immunoimaging in a subject, compositions and kits comprising said conjugates and methods of in vivo immunoimaging of superoxide dismutase (SOD1) useful as a marker of amyotrophic lateral sclerosis (ALS) or efficacy of drug therapy of ALS in subject using these conjugates. Furthermore, SOD1-antibodies specific for misfolded and/or aggregated SOD1 are provided for use in treatment of bone and/or joint related diseases.
Claims45
A labeled-antibody conjugate for use in a method of diagnosing amyotrophic lateral sclerosis (ALS) or monitoring drug therapy and/or progression of ALS in a subject, wherein the method comprises in vivo immunoimaging of misfolded SOD1 in a subject and the labeled-antibody conjugate comprises:
- (a) an antibody that specifically binds to misfolded SOD1;
- and
- (b) a detection label conjugated to the antibody.
The labeled-antibody conjugate for use according to any one of the preceding claims, wherein the detection label is conjugated to the antibody with a bifunctional chelator or prosthetic group, preferably wherein the bifunctional chelator or prosthetic group is conjugated randomly on lysine residues of the antibody.
The labeled-antibody conjugate for use according to any one of the preceding claims, wherein the antibody is characterized by comprising in its variable region, i.e., binding domain the six CDRs of the variable heavy (VH) and variable light (VL) chain, wherein:
- (a) VH-CDR1 comprises the amino acid sequence of SEQ ID NO:
- 3 or a variant thereof, wherein the variant comprises one or two amino acid substitutions,
- (b) VH-CDR2 comprises the amino acid sequence of SEQ ID NO:
- 4 or a variant thereof, wherein the variant comprises one or two amino acid substitutions,
- (c) VH-CDR3 comprises the amino acid sequence of SEQ ID NO:
- 5 or a variant thereof, wherein the variant comprises one or two amino acid substitutions,
- (d) VL-CDR1 comprises the amino acid sequence of SEQ ID NO:
- 8 or a variant thereof, wherein the variant comprises one or two amino acid substitutions,
- (e) VL-CDR2 comprises the amino acid sequence of SEQ ID NO:
- 9 or a variant thereof, wherein the variant comprises one or two amino acid substitutions, and
- (f) VL-CDR3 comprises the amino acid sequence of SEQ ID NO:
- 10 or a variant thereof, wherein the variant comprises one or two amino acid substitutions.
The labeled-antibody conjugate for use according to any one of the preceding claims, wherein the antibody is characterized by comprising in its variable region, i.e., binding domain a VH chain and a VL chain, wherein
- (a) the VH chain comprises the amino acid sequence depicted in SEQ ID NO:
- 1 or 2 or a variant thereof, wherein the variant comprises one or more amino acid substitutions;
- and
- (b) the VL chain comprises the amino acid sequence depicted in SEQ ID NO:
- 6 or 7, or a variant thereof, wherein the variant comprises one or more amino acid substitutions;
- preferably wherein the VH and VL chain amino acid sequence is at least 90% identical to SEQ ID NO:
- 1 or 2 and 6 or 7, respectively.
The labeled antibody conjugate for use according to any of the preceding claims, wherein the antibody comprises
- two heavy chains, wherein each heavy chain comprises the amino acid sequence depicted in SEQ ID NO:
- 14;
- and
- two light chains, wherein each light chain each light chain comprises the amino acid sequence depicted in SEQ ID NO:
- 15.
The labeled-antibody conjugate for use according to any one of the preceding claims, wherein the antibody is AP-101.
The labeled-antibody conjugate for use according to any one of the preceding claims, wherein the antibody is glycosylated or deglycosylated.
The labeled-antibody conjugate for use according to any one of the preceding claims, wherein the imaging comprises positron emission tomography (PET) imaging, single photon emission computed tomography (SPECT) imaging, or combinations thereof with computed tomography (CT).
A drug for use in the treatment of ALS in a subject which (i) has been diagnosed for suffering or developing ALS and/or (ii) is monitored for efficacy of drug therapy and/or disease progression of ALS by a method as defined in any one of the preceding claims, preferably wherein the drug is selected from Riluzole (Rilutek®), Edaravone (Radicava®), Tofersen (BIIB067), AP-101, dextromethorphan HBr and quinidine sulfate (Nuedexta®), Reldesemtiv (CY5031), Arimoclomol, Levosimendan, Fasudil, pyrimethamine, (Daraprim™), rapamycin, baclofen (Gablofen®, Kemstro®, Lioresal®), diazepam (Diastat®, Valium®), amitriptyline (Elavil®), trihexyphenidyl, Scopoderm® (scopolamine patch), glycopyrrolate (Robinul®), Ravulizumab (BNJ441, ALXN1210, or Ultomiris®) and Eculizumab (Soliris®).
A labeled-antibody conjugate as defined in any one of the preceding claims.
An antibody that specifically binds to misfolded SOD1, which comprises a bifunctional chelator, preferably wherein the bifunctional chelator is p-SCN-Bn desferoxamine (SCN-Bn-DFO).
An anti-SOD1 antibody or equivalent SOD1 binding molecule for use in targeting misfolded and/or aggregated SOD1 in bone and/or joints of a subject, preferably wherein the antibody is the AP-101 antibody.
89Zr or 89Zr-DFO for use in immunoimaging of misfolded and/or aggregated SOD1 in a subject, preferably for use in the labeled antibody conjugate or method of any one of the preceding claims and/or for use in early diagnostic of ALS and/or in the monitoring of therapeutic interventions of ALS.
Dependencies are inferred from the claim text.