High affinity anti-CD3 antibodies, and methods for their generation and use

Patent metadata

Field	Value
Publication number	US-12552863-B2
Application number	US-202017617046-A
Country	US
Kind code	B2
Filing date	Jun 8, 2020
Priority date	Jun 7, 2019
Publication date	Feb 17, 2026
Grant date	Feb 17, 2026

Abstract

Antibodies and antigen-binding fragments thereof with high affinity for CD3 and desirable developability profiles are provided, as well as methods for their manufacture and use.

First claim

What is claimed is:

1 . An anti-cluster of differentiation three (CD3) antibody or antigen-binding antibody fragment, which comprises:
a. a heavy chain variable region (VH) polypeptide comprising:
i. a VH CDR1 (CDRH1) comprising FNIKDYYMH (SEQ ID NO: 13);
ii. a VH CDR2 (CDRH2) comprising WIDLENANTVYDAKFQG (SEQ ID NO: 15); and
iii. a VH CDR3 (CDRH3) comprising ARDAYGRYFYDV (SEQ ID NO: 103); and
b. a light chain variable region (VL) polypeptide comprising:
i. a VL CDR1 (CDRL1) comprising KSSQSLLNARTGKNYLA (SEQ ID NO: 8);
ii. a VL CDR2 (CDRL2) comprising WASTRX 1 S (SEQ ID NO: 133); and
iii. a VL CDR3 (CDRL3) comprising X 2 QSYFRRT (SEQ ID NO: 134);
wherein:
(i) X 1 is S and X 2 is V;
(ii) X 1 is E and X 2 is V; or
(iii) X 1 is E and X 2 is A.

2 . The anti-CD3 antibody or antigen-binding antibody fragment of claim 1 , which:
(i) binds to human CD3 with a dissociation constant (K D ) of about 200 pM or less; and/or (ii) elicits T cell activation or T cell killing while displaying a decreased propensity to elicit cytokine production to levels capable of inducing cytokine release syndrome.

3 . The anti-CD3 antibody or antigen-binding antibody fragment of claim 1 , which comprises one or more of the following features:
a. comprises an scFv, a Fv, a Fab, a Fab′, a Fab′-SH, a F(ab′)2, a diabody, a scFv2-Fc2, or a scFv-IgG; b. comprises:
(A) a heavy chain comprising the VH polypeptide and a heavy chain constant region (CH) polypeptide; and
(B) a light chain comprising the VL polypeptide and a light chain constant region (CL) polypeptide;
c. comprises an IgG, IgA, IgD, IgE, or IgM antibody; d. is comprised in a chimeric antigen receptor (CAR), which comprises at least one transmembrane domain, at least one intracellular domain from a T-cell receptor, and at least one co-stimulatory domain; e. comprises an IgG constant domain.

4 . An isolated or recombinant nucleic acid encoding an anti-CD3 antibody or antigen-binding antibody fragment of claim 1 , or an expression vector containing said nucleic acid.

5 . A host cell transfected, transformed, or transduced with a nucleic acid according to claim 4 , or with a vector containing said nucleic acid sequence.

6 . A pharmaceutical composition comprising: an anti-CD3 antibody or antigen-binding antibody fragment of claim 1 ; and a pharmaceutically acceptable carrier and/or excipient.

7 . An anti-CD3 antibody or antigen-binding antibody fragment, which comprises:
(A) a heavy chain variable region (VH) polypeptide comprising a VH CDR1 (CDRH1), a VH CDR2 (CDRH2), and a VH CDR3 (CDRH3); and (B) a light chain variable region (VL) polypeptide comprising a VL CDR1 (CDRL1), a VL CDR2 (CDRL2), and a VL CDR3 (CDRL3), wherein: (I) (i) (a) the amino acid sequences of the CDRH1, the CDRH2, and the CDRH3 comprise or consist of the heavy chain CDR 1, 2, and 3 sequences, respectively, contained in SEQ ID NO: 17, and
(b) the amino acid sequences of the CDRL1, the CDRL2, and the CDRL3 comprise or consist of the light chain CDR 1, 2, and 3 sequences, respectively, contained in SEQ ID NO: 34; or
(ii) the amino acid sequences of the CDRH1, the CDRH2, the CDRH3, the CDRL1, the CDRL2, and the CDRL3 comprise or consist of SEQ ID NO: 13, 15, 103, 8, 11, and 4, respectively;
(II) (i) (a) the amino acid sequences of the CDRH1, the CDRH2, and the CDRH3 comprise or consist of the heavy chain CDR 1, 2, and 3 sequences, respectively, contained in SEQ ID NO: 22, and
(b) the amino acid sequences of the CDRL1, the CDRL2, and the CDRL3 comprise or consist of the light chain CDR 1, 2, and 3 sequences, respectively, contained in SEQ ID NO: 23; or
(ii) the amino acid sequences of the CDRH1, the CDRH2, the CDRH3, the CDRL1, the CDRL2, and the CDRL3 comprise or consist of SEQ ID NO: 13, 15, 103, 8, 10, and 4, respectively;
(III) (i) (a) the amino acid sequences of the CDRH1, the CDRH2, and the CDRH3 comprise or consist of the heavy chain CDR 1, 2, and 3 sequences, respectively, contained in SEQ ID NO: 29, and
(b) the amino acid sequences of the CDRL1, the CDRL2, and the CDRL3 comprise or consist of the light chain CDR 1, 2, and 3 sequences, respectively, contained in SEQ ID NO: 23; or
(ii) the amino acid sequences of the CDRH1, the CDRH2, the CDRH3, the CDRL1, the CDRL2, and the CDRL3 comprise or consist of SEQ ID NO: 13, 15, 103, 8, 10, and 4, respectively;
(IV) (i) (a) the amino acid sequences of the CDRH1, the CDRH2, and the CDRH3 comprise or consist of the heavy chain CDR 1, 2, and 3 sequences, respectively, contained in SEQ ID NO: 49, and
(b) the amino acid sequences of the CDRL1, the CDRL2, and the CDRL3 comprise or consist of the light chain CDR 1, 2, and 3 sequences, respectively, contained in SEQ ID NO: 23; or
(ii) the amino acid sequences of the CDRH1, the CDRH2, the CDRH3, the CDRL1, the CDRL2, and the CDRL3 comprise or consist of SEQ ID NO: 13, 15, 103, 8, 10, and 4, respectively;
(V) (i) (a) the amino acid sequences of the CDRH1, the CDRH2, and the CDRH3 comprise or consist of the heavy chain CDR 1, 2, and 3 sequences, respectively, contained in SEQ ID NO: 58, and
(b) the amino acid sequences of the CDRL1, the CDRL2, and the CDRL3 comprise or consist of the light chain CDR 1, 2, and 3 sequences, respectively, contained in SEQ ID NO: 23; or
(ii) the amino acid sequences of the CDRH1, the CDRH2, the CDRH3, the CDRL1, the CDRL2, and the CDRL3 comprise or consist of SEQ ID NO: 13, 15, 103, 8, 10, and 4, respectively;
(VI) (i) (a) the amino acid sequences of the CDRH1, the CDRH2, and the CDRH3 comprise or consist of the heavy chain CDR 1, 2, and 3 sequences, respectively, contained in SEQ ID NO: 59, and
(b) the amino acid sequences of the CDRL1, the CDRL2, and the CDRL3 comprise or consist of the light chain CDR 1, 2, and 3 sequences, respectively, contained in SEQ ID NO: 23; or
(ii) the amino acid sequences of the CDRH1, the CDRH2, the CDRH3, the CDRL1, the CDRL2, and the CDRL3 comprise or consist of SEQ ID NO: 13, 15, 103, 8, 10, and 4, respectively;
(VII) (i) (a) the amino acid sequences of the CDRH1, the CDRH2, and the CDRH3 comprise or consist of the heavy chain CDR 1, 2, and 3 sequences, respectively, contained in SEQ ID NO: 70, and
(b) the amino acid sequences of the CDRL1, the CDRL2, and the CDRL3 comprise or consist of the light chain CDR 1, 2, and 3 sequences, respectively, contained in SEQ ID NO: 23; or
(ii) the amino acid sequences of the CDRH1, the CDRH2, the CDRH3, the CDRL1, the CDRL2, and the CDRL3 comprise or consist of SEQ ID NO: 13, 15, 103, 8, 10, and 4, respectively;
(VIII) (i) (a) the amino acid sequences of the CDRH1, the CDRH2, and the CDRH3 comprise or consist of the heavy chain CDR 1, 2, and 3 sequences, respectively, contained in SEQ ID NO: 24, and
(b) the amino acid sequences of the CDRL1, the CDRL2, and the CDRL3 comprise or consist of the light chain CDR 1, 2, and 3 sequences, respectively, contained in SEQ ID NO: 25; or
(ii) the amino acid sequences of the CDRH1, the CDRH2, the CDRH3, the CDRL1, the CDRL2, and the CDRL3 comprise or consist of SEQ ID NO: 13, 15, 103, 8, 10, and 2, respectively;
(IX) (i) (a) the amino acid sequences of the CDRH1, the CDRH2, and the CDRH3 comprise or consist of the heavy chain CDR 1, 2, and 3 sequences, respectively, contained in SEQ ID NO: 17, and
(b) the amino acid sequences of the CDRL1, the CDRL2, and the CDRL3 comprise or consist of the light chain CDR 1, 2, and 3 sequences, respectively, contained in SEQ ID NO: 47; or
(ii) the amino acid sequences of the CDRH1, the CDRH2, the CDRH3, the CDRL1, the CDRL2, and the CDRL3 comprise or consist of SEQ ID NO: 13, 15, 103, 8, 10, and 2, respectively;
(X) (i) (a) the amino acid sequences of the CDRH1, the CDRH2, and the CDRH3 comprise or consist of the heavy chain CDR 1

Assignees

• Adimab Llc

Inventors

• Pejchal Robert
• Stein Caitlin
• Mccreary Julia

Classifications

• C07K2317/92

  Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value · CPC title

• C07K2317/622

  Single chain antibody (scFv) · CPC title

• C07K2317/31

  multispecific · CPC title

• A61K2039/505

  comprising antibodies · CPC title

• C07K2317/55

  Fab or Fab' · CPC title