CYSTEINE ENGINEERED ANTIBODIES AND CONJUGATES

• US 20110137017A1
• Filed: 12/17/2010
• Published: 06/09/2011
• Est. Priority Date: 09/23/2004
• Status: Abandoned Application

• Current Assignee: Charles W. Eigenbrot, Helga E. Raab, Henry Lowman, Jagath Reddy Junutula, Richard Vandlen
• Original Assignee: Charles W. Eigenbrot, Helga E. Raab, Henry Lowman, Jagath Reddy Junutula, Richard Vandlen
• Inventors: Raab, Helga E., Eigenbrot, Charles W., Lowman, Henry, Junutula, Jagath Reddy, Vandlen, Richard
• Application Number:
  US12/971,197
• Publication Number:
  US 20110137017A1
• Time in Patent Office: Days
• US Class Current: 530/387.3
• CPC Class Codes: A01K 2267/0331 Animal model for proliferative diseases
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 47/6803 Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
• CPC Class Codes: A61K 47/6817 Toxins
• CPC Class Codes: A61K 47/6851 the antibody targeting a determinant of a tumour cell
• CPC Class Codes: A61K 47/6889 Conjugates wherein the antibody being the modifying agent and wherein the linker, binder or spacer confers particular properties to the conjugates, e.g. peptidic enzyme-labile linkers or acid-labile linkers, providing for an acid-labile immuno conjugate wherein the drug may be released from its antibody conjugated part in an acidic, e.g. tumoural or environment
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07K 16/00 Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies antibodies with enzymatic activity, e.g. abzymes C12N9/0002
• CPC Class Codes: C07K 16/32 against translation products of oncogenes
• CPC Class Codes: C07K 2317/21 from primates, e.g. man
• CPC Class Codes: C07K 2317/51 Complete heavy chain or Fd fragment, i.e. VH + CH1
• CPC Class Codes: C07K 2317/52 Constant or Fc region; Isotype
• CPC Class Codes: C07K 2317/55 Fab or Fab'
• CPC Class Codes: C07K 2317/624 Disulfide-stabilized antibody (dsFv)

Abstract

Antibodies are engineered by replacing one or more amino acids of a parent antibody with non cross-linked, highly reactive cysteine amino acids. Antibody fragments may also be engineered with one or more cysteine amino acids to form cysteine engineered antibody fragments (ThioFab). Methods of design, preparation, screening, and selection of the cysteine engineered antibodies are provided. Cysteine engineered antibodies (Ab), optionally with an albumin-binding peptide (ABP) sequence, are conjugated with one or more drug moieties (D) through a linker (L) to form cysteine engineered antibody-drug conjugates having Formula I:

Ab-(L-D)_p  I

where p is 1 to 4. Diagnostic and therapeutic uses for cysteine engineered antibody drug compounds and compositions are disclosed.

Claims

1. A cysteine engineered antibody comprising one or more variable region heavy chain sequences with a free cysteine amino acid selected from SEQ ID NOS:

9-16;

4. The cysteine engineered antibody of any one of claims 1-3 wherein the free cysteine amino acid is conjugated to a drug moiety selected from a maytansinoid, an auristatin, a dolastatin, or a calicheamicin.

2. A cysteine engineered antibody comprising one or more Fc constant region heavy chain sequences with a free cysteine amino acid selected from SEQ ID NOS:

31, 33, 36, 37 and 38;

3. A cysteine engineered antibody comprising one or more variable region heavy chain sequences with a free cysteine amino acid selected from SEQ ID NOS:

40-44;