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US 2024/0199744 A1Published application
Therapeutic methods using constrained conditionally activated binding proteins
AssigneeTakeda Pharmaceutical Company Limited
InventorsChad Michael May, Robert B. DuBridge, Maia Vinogradova, Anand Panchal
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Abstract
The invention relates to COnditional Bispecific Redirected Activation constructs, or COBRAs, that are administered in an active pro-drug format. Upon exposure to tumor proteases, the constructs are cleaved and activated, such that they can bind both tumor target antigens (TTAs) as well as CD3, thus recruiting T cells expressing CD3 to the tumor, resulting in treatment.
Claims76
A method for treating cancer in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a polypeptide comprising, from N- to C-terminus:
- a) a first single domain antigen binding domain (sdABD) that binds to a first human tumor target antigen (TTA);
- b) a first domain linker;
- c) a constrained Fv domain comprising:
- i) a first variable heavy domain comprising a vhCDR1, vhCDR2 and vhCDR3;
- ii) a constrained non-cleavable linker (CNCL);
- and
- iii) a first variable light domain comprising vlCDR1, vlCDR2 and vlCDR3, wherein the CNCL is positioned between the first variable heavy domain and the first variable light domain and prevents the first variable heavy domain and the first variable light domain from interacting to form an active Fv capable of binding CD3;
- d) a second domain linker;
- e) a second sdABD that binds to a second human TTA;
- f) a cleavable linker (CL);
- g) a pseudo Fv domain comprising:
- i) a first pseudo variable light domain;
- ii) a non-cleavable linker (NCL);
- and
- iii) a first pseudo variable heavy domain:
- h) a third domain linker;
- and
- i) a third sdABD that binds to human serum albumin;
- wherein:
- the first variable heavy domain and the first variable light domain are capable of binding human CD3 but said constrained Fv domain does not bind CD3;
- and
- the polypeptide does not bind CD3 when the CL is intact.
19 more elements
A method for treating cancer in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a polypeptide comprising, from N- to C-terminus:
- a) a first single domain antigen binding domain (sdABD) that binds to human serum albumin;
- b) a first domain linker;
- c) a pseudo Fv domain comprising:
- i) a first pseudo variable light domain;
- ii) a non-cleavable linker (NCL);
- and
- iii) a first pseudo variable heavy domain;
- d) a cleavable linker (CL);
- e) a second sdABD that binds to a first human tumor target antigen (TTA);
- f) a second domain linker;
- g) a constrained Fv domain comprising:
- i) a second variable heavy domain comprising a vhCDR1, vhCDR2 and vhCDR3;
- ii) a constrained non-cleavable linker (CNCL);
- and
- iii) a first variable light domain comprising vlCDR1, vlCDR2 and vlCDR3, wherein the CNCL is positioned between the first variable heavy domain and the first variable light domain and prevents the first variable heavy domain and the first variable light domain from interacting to form an active Fv capable of binding CD3;
- h) a third domain linker;
- i) a third second sdABD that binds to a second human TTA:
- wherein:
- the first variable heavy domain and the first variable light domain are capable of binding human CD3 but said constrained Fv domain does not bind CD3;
- and
- the polypeptide does not bind CD3 when the CL is intact.
18 more elements
A method for treating a colorectal cancer in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a polypeptide comprising, from N- to C-terminus:
- a) a first single domain antigen binding domain (sdABD) that binds to a first human tumor target antigen (TTA);
- b) a first domain linker;
- c) a constrained Fv domain comprising:
- i) a first variable heavy domain comprising a vhCDR1, vhCDR2 and vhCDR3;
- ii) a constrained non-cleavable linker (CNCL);
- and
- iii) a first variable light domain comprising vlCDR1, vlCDR2 and vlCDR3, wherein the CNCL is positioned between the first variable heavy domain and the first variable light domain and prevents the first variable heavy domain and the first variable light domain from interacting to form an active Fv capable of binding CD3;
- d) a second domain linker;
- e) a second sdABD that binds to a second human TTA;
- f) a cleavable linker (CL);
- g) a pseudo Fv domain comprising:
- i) a first pseudo variable light domain;
- ii) a non-cleavable linker (NCL);
- and
- iii) a first pseudo variable heavy domain;
- h) a third domain linker;
- and
- i) a third sdABD that binds to human serum albumin;
- wherein:
- at least one of the first human TTA and the second human TTA is EGFR;
- the first variable heavy domain and the first variable light domain are capable of binding human CD3 but said constrained Fv domain does not bind CD3;
- and
- the polypeptide does not bind CD3 when the CL is intact.
20 more elements
A method for treating a colorectal cancer in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a polypeptide comprising, from N- to C-terminus:
- a) a first single domain antigen binding domain (sdABD) that binds to human serum albumin;
- b) a first domain linker;
- c) a pseudo Fv domain comprising:
- i) a first pseudo variable light domain;
- ii) a non-cleavable linker (NCL);
- and
- iii) a first pseudo variable heavy domain;
- d) a cleavable linker (CL);
- e) a second sdABD that binds to a first human tumor target antigen (TTA);
- f) a second domain linker;
- g) a constrained Fv domain comprising:
- i) a second variable heavy domain comprising a vhCDR1, vhCDR2 and vhCDR3;
- ii) a constrained non-cleavable linker (CNCL);
- and
- iii) a first variable light domain comprising vlCDR1, vlCDR2 and vlCDR3, wherein the CNCL is positioned between the first variable heavy domain and the first variable light domain and prevents the first variable heavy domain and the first variable light domain from interacting to form an active Fv capable of binding CD3;
- h) a third domain linker;
- i) a third second sdABD that binds to a second human TTA;
- wherein:
- at least one of the first human TTA and the second human TTA is EGFR;
- the first variable heavy domain and the first variable light domain are capable of binding human CD3 but said constrained Fv domain does not bind CD3;
- and
- the polypeptide does not bind CD3 when the CL is intact.
19 more elements
A method for treating a head and neck squamous cell carcinoma in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a polypeptide comprising, from N- to C-terminus:
- a) a first single domain antigen binding domain (sdABD) that binds to a first human tumor target antigen (TTA);
- b) a first domain linker;
- c) a constrained Fv domain comprising:
- i) a first variable heavy domain comprising a vhCDR1, vhCDR2 and vhCDR3;
- ii) a constrained non-cleavable linker (CNCL);
- and
- iii) a first variable light domain comprising vlCDR1, vlCDR2 and vlCDR3, wherein the CNCL is positioned between the first variable heavy domain and the first variable light domain and prevents the first variable heavy domain and the first variable light domain from interacting to form an active Fv capable of binding CD3;
- d) a second domain linker;
- e) a second sdABD that binds to a second human TTA;
- f) a cleavable linker (CL);
- g) a pseudo Fv domain comprising:
- i) a first pseudo variable light domain;
- ii) a non-cleavable linker (NCL);
- and
- iii) a first pseudo variable heavy domain;
- h) a third domain linker;
- and
- i) a third sdABD that binds to human serum albumin;
- wherein:
- at least one of the first human TTA and the second human TTA is B7H3;
- the first variable heavy domain and the first variable light domain are capable of binding human CD3 but said constrained Fv domain does not bind CD3;
- and
- the polypeptide does not bind CD3 when the CL is intact.
20 more elements
A method for treating a head and neck squamous cell carcinoma in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a polypeptide comprising, from N- to C-terminus:
- a) a first single domain antigen binding domain (sdABD) that binds to human serum albumin;
- b) a first domain linker;
- c) a pseudo Fv domain comprising:
- i) a first pseudo variable light domain;
- ii) a non-cleavable linker (NCL);
- and
- iii) a first pseudo variable heavy domain;
- d) a cleavable linker (CL);
- e) a second sdABD that binds to a first human tumor target antigen (TTA);
- f) a second domain linker;
- g) a constrained Fv domain comprising:
- i) a second variable heavy domain comprising a vhCDR1, vhCDR2 and vhCDR3;
- ii) a constrained non-cleavable linker (CNCL);
- and
- iii) a first variable light domain comprising vlCDR1, vlCDR2 and vlCDR3, wherein the CNCL is positioned between the first variable heavy domain and the first variable light domain and prevents the first variable heavy domain and the first variable light domain from interacting to form an active Fv capable of binding CD3;
- h) a third domain linker;
- i) a third second sdABD that binds to a second human TTA;
- wherein:
- at least one of the first human TTA and the second human TTA is B7H3;
- the first variable heavy domain and the first variable light domain are capable of binding human CD3 but said constrained Fv domain does not bind CD3;
- and
- the polypeptide does not bind CD3 when the CL is intact.
19 more elements
Dependencies are inferred from the claim text.