Anti-cd27 and anti-pd-l1 antibodies and bispecific constructs
AssigneeCelldex Therapeutics, Inc.
InventorsTibor KELER, Joel GOLDSTEIN, Laura A. VITALE, Lizhen HE
Life of this patent
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Abstract
Provided herein are novel anti-CD27 and anti-PD-L1 antibodies, and binding domains thereof, as well as bispecific constructs and anti-CD27 binding domain linked to an anti-PD-L1 binding domain. Also provided herein are methods of stimulating T cell activity, methods of inducing or enhancing an immune response, and methods of treating a disease or condition (e.g., cancer) by administering the bispecific constructs, antibodies, or antigen binding fragments thereof, or compositions described herein to a patient in need thereof.
Claims124
A bispecific construct comprising an anti-CD27 binding domain linked to an anti-PD-L1 binding domain, wherein:
- (i) the anti-CD27 binding domain comprises:
- a. heavy chain variable region CDR1, CDR2 and CDR3 as set forth in SEQ ID NOs:1, 2, and 3, respectively, or conservative sequence modifications thereof, and light chain variable region CDR1, CDR2 and CDR3 as set forth in SEQ ID NOs:4, 5, and 6, respectively, or conservative sequence modifications thereof, or
- b. heavy chain variable region CDR1, CDR2 and CDR3 as set forth in SEQ ID NOs:7, 8, and 9, respectively, or conservative sequence modifications thereof, and light chain variable region CDR1, CDR2 and CDR3 as set forth in SEQ ID NOs:10, 11, and 12, respectively, or conservative sequence modifications thereof;
- and
- (ii) the anti-PD-L1 binding domain comprises:
- a. a heavy chain variable region CDR1 comprising an amino acid sequence selected from the consensus sequence:
- (T,S)(S,Y,H)WMS (SEQ ID NO:167) or conservative sequence modifications thereof;
- b. a heavy chain variable region CDR2 comprising SEQ ID NO:168 or conservative sequence modifications thereof;
- c. a heavy chain variable region CDR3 comprising SEQ ID NO:169 or conservative sequence modifications thereof;
- d. a light chain variable region CDR1 comprising SEQ ID NO:170 or conservative sequence modifications thereof;
- e. a light chain variable region CDR2 comprising SEQ ID NO:171 or conservative sequence modifications thereof;
- and
- f. a light chain variable region CDR3 comprising SEQ ID NO:172 or conservative sequence modifications thereof.
A bispecific construct comprising an anti-CD27 binding domain linked to an anti-PD-L1 binding domain, wherein:
- (i) the anti-CD27 binding domain comprises:
- a. heavy chain variable region CDR1, CDR2 and CDR3 as set forth in SEQ ID NOs:1, 2, and 3, respectively, or conservative sequence modifications thereof, and light chain variable region CDR1, CDR2 and CDR3 as set forth in SEQ ID NOs:4, 5, and 6, respectively, or conservative sequence modifications thereof, or
- b. heavy chain variable region CDR1, CDR2 and CDR3 as set forth in SEQ ID NOs:7, 8, and 9, respectively, or conservative sequence modifications thereof, and light chain variable region CDR1, CDR2 and CDR3 as set forth in SEQ ID NOs:10, 11, and 12, respectively;
- or conservative sequence modifications thereof and
- (ii) the anti-PD-L1 binding domain comprises:
- a. a heavy chain variable region comprising SEQ ID NO:77 and a light chain variable region comprising SEQ ID NO:78 or sequences at least 95% identical thereto;
- b. a heavy chain variable region comprising SEQ ID NO:79 and a light chain variable region comprising SEQ ID NO:80 or sequences at least 95% identical thereto;
- c. a heavy chain variable region comprising SEQ ID NO:81 and a light chain variable region comprising SEQ ID NO:82 or sequences at least 95% identical thereto;
- d. a heavy chain variable region comprising SEQ ID NO:83 and a light chain variable region comprising SEQ ID NO:84 or sequences at least 95% identical thereto;
- e. a heavy chain variable region comprising SEQ ID NO:85 and a light chain variable region comprising SEQ ID NO:86 or sequences at least 95% identical thereto;
- or
- f. a heavy chain variable region comprising SEQ ID NO:87 and a light chain variable region comprising SEQ ID NO:88 or sequences at least 95% identical thereto.
The bispecific construct of any one of the preceding claims wherein (a) the anti-PD-L1 binding domain further comprises a human IgG1 constant domain or (b) the anti-CD27 binding domain further comprises a human IgG1 constant domain.
The bispecific construct of any one of the preceding claims, wherein (a) the anti-CD27 binding domain is linked to the C-terminus of the heavy chain of the anti-PD-L1 binding domain or (b) the anti-PD-L1 binding domain is linked to the C-terminus of the heavy chain of the anti-CD27 binding domain.
The bispecific construct of any one of the preceding claims, wherein the anti-CD27 binding domain is a scFv or (b) the anti-PD-L1 binding domain is a scFv.
The bispecific construct of any one of the preceding claims, wherein the anti-PD-L1 binding domain and the anti-CD27 binding domain are genetically fused.
The bispecific construct of any one of the preceding claims, wherein the anti-PD-L1 binding domain and the anti-CD27 binding domain are chemically conjugated.
A bispecific construct comprising an anti-PD-L1 antibody linked to an anti-CD27 scFv, wherein:
- (i) the anti-CD27 scFv comprises:
- a. heavy chain variable region CDR1, CDR2 and CDR3 as set forth in SEQ ID NOs:1, 2, and 3, respectively, or conservative sequence modifications thereof, and light chain variable region CDR1, CDR2 and CDR3 as set forth in SEQ ID NOs:4, 5, and 6, respectively, or conservative sequence modifications thereof, or
- b. heavy chain variable region CDR1, CDR2 and CDR3 as set forth in SEQ ID NOs:7, 8, and 9, respectively, or conservative sequence modifications thereof, and light chain variable region CDR1, CDR2 and CDR3 as set forth in SEQ ID NOs:10, 11, and 12, respectively, or conservative sequence modifications thereof;
- and
- (ii) the anti-PD-L1 antibody comprises:
- a. heavy chain variable region CDR1, CDR2 and CDR3 as set forth in SEQ ID NOs:
- 29, 30, and 31, respectively, or conservative sequence modifications thereof, and light chain variable region CDR1, CDR2 and CDR3 as set forth in SEQ ID NOs:32, 33, and 34, respectively, or conservative sequence modifications thereof;
- b. heavy chain variable region CDR1, CDR2 and CDR3 as set forth in SEQ ID NOs:
- 35, 36, and 37, respectively, or conservative sequence modifications thereof, and light chain variable region CDR1, CDR2 and CDR3 as set forth in SEQ ID NOs:38, 39, and 40, respectively, or conservative sequence modifications thereof;
- c. heavy chain variable region CDR1, CDR2 and CDR3 as set forth in SEQ ID NOs:
- 41, 42, and 43, respectively, or conservative sequence modifications thereof, and light chain variable region CDR1, CDR2 and CDR3 as set forth in SEQ ID NOs:44, 45, and 46, respectively, or conservative sequence modifications thereof;
- d. heavy chain variable region CDR1, CDR2 and CDR3 as set forth in SEQ ID NOs:
- 47, 48, and 49, respectively, or conservative sequence modifications thereof, and light chain variable region CDR1, CDR2 and CDR3 as set forth in SEQ ID NOs:50, 51, and 52, respectively, or conservative sequence modifications thereof;
- e. heavy chain variable region CDR1, CDR2 and CDR3 as set forth in SEQ ID NOs:
- 53, 54, and 55, respectively, or conservative sequence modifications thereof, and light chain variable region CDR1, CDR2 and CDR3 as set forth in SEQ ID NOs:56, 57, and 58, respectively, or conservative sequence modifications thereof;
- or
- f. heavy chain variable region CDR1, CDR2 and CDR3 as set forth in SEQ ID NOs:
- 59, 60, and 61, respectively, or conservative sequence modifications thereof, and light chain variable region CDR1, CDR2 and CDR3 as set forth in SEQ ID NOs:62, 63, and 64, respectively, or conservative sequence modifications thereof;
- and
- g. a human IgG1 constant domain;.
A bispecific construct comprising an anti-PD-L1 antibody linked to an anti-CD27 scFv, wherein:
- (i) the anti-CD27 scFv comprises:
- a. a heavy chain variable region comprising SEQ ID NO:17 and a light chain variable region comprising SEQ ID NO:18;
- or
- b. a heavy chain variable region comprising SEQ ID NO:19 and a light chain variable region comprising SEQ ID NO:20;
- and
- (ii) the anti-PD-L1 antibody comprises:
- a. a heavy chain variable region comprising SEQ ID NO:77 and a light chain variable region comprising SEQ ID NO:78;
- b. a heavy chain variable region comprising SEQ ID NO:79 and a light chain variable region comprising SEQ ID NO:80;
- c. a heavy chain variable region comprising SEQ ID NO:81 and a light chain variable region comprising SEQ ID NO:82;
- d. a heavy chain variable region comprising SEQ ID NO:83 and a light chain variable region comprising SEQ ID NO:84;
- e. a heavy chain variable region comprising SEQ ID NO:85 and a light chain variable region comprising SEQ ID NO:86;
- or
- f. a heavy chain variable region comprising SEQ ID NO:87 and a light chain variable region comprising SEQ ID NO:88;
- and
- g. a human IgG1 constant domain.
A bispecific construct comprising an anti-PD-L1 antibody linked to an anti-CD27 scFv, wherein:
- (i) the anti-CD27 scFv comprises heavy chain variable region CDR1, CDR2 and CDR3 as set forth in SEQ ID NOs:7, 8, and 9, respectively, or conservative sequence modifications thereof, and light chain variable region CDR1, CDR2 and CDR3 as set forth in SEQ ID NOs:10, 11, and 12, respectively, or conservative sequence modifications thereof;
- and
- (ii) the anti-PD-L1 antibody comprises a heavy chain variable region CDR1, CDR2 and CDR3 as set forth in SEQ ID NOs:
- 47, 48, and 49, respectively, or conservative sequence modifications thereof, and light chain variable region CDR1, CDR2 and CDR3 as set forth in SEQ ID NOs:50, 51, and 52, respectively, or conservative sequence modifications thereof;
- and a human IgG1 constant domain.
A bispecific construct comprising an anti-PD-L1 antibody linked to an anti-CD27 scFv, wherein:
- (i) the anti-CD27 scFv comprises a heavy chain variable region comprising SEQ ID NO:19, a light chain variable region comprising SEQ ID NO:20;
- and
- (ii) the anti-PD-L1 antibody comprises a heavy chain variable region comprising SEQ ID NO:83 and a light chain variable region comprising SEQ ID NO:84, and a human IgG1 constant domain.
A bispecific construct comprising an anti-PD-L1 antibody linked to an anti-CD27 scFv, wherein:
- (i) the anti-CD27 scFv comprises heavy chain variable region CDR1, CDR2 and CDR3 as set forth in SEQ ID NOs:7, 8, and 9, respectively, or conservative sequence modifications thereof, and light chain variable region CDR1, CDR2 and CDR3 as set forth in SEQ ID NOs:10, 11, and 12, respectively, or conservative sequence modifications thereof;
- and
- (ii) the anti-PD-L1 antibody comprises heavy chain variable region CDR1, CDR2 and CDR3 as set forth in SEQ ID NOs:59, 60, and 61, respectively, or conservative sequence modifications thereof, and light chain variable region CDR1, CDR2 and CDR3 as set forth in SEQ ID NOs:62, 63, and 64, respectively or conservative sequence modifications thereof, and a human IgG1 constant domain.
A bispecific construct comprising an anti-PD-L1 antibody linked to an anti-CD27 scFv, wherein:
- (i) the anti-CD27 scFv comprises a heavy chain variable region comprising SEQ ID NO:19, a light chain variable region comprising SEQ ID NO:20;
- and
- (ii) the anti-PD-L1 antibody comprises a heavy chain variable region comprising SEQ ID NO:87 and a light chain variable region comprising SEQ ID NO:88, and a human IgG1 constant domain.
A bispecific construct comprising an anti-CD27 antibody linked to an anti-PD-L1 scFv, wherein:
- (i) the anti-CD27 antibody comprises:
- a. heavy chain variable region CDR1, CDR2 and CDR3 as set forth in SEQ ID NOs:1, 2, and 3, respectively, or conservative sequence modifications thereof, and light chain variable region CDR1, CDR2 and CDR3 as set forth in SEQ ID NOs:4, 5, and 6, respectively, or conservative sequence modifications thereof, or
- b. heavy chain variable region CDR1, CDR2 and CDR3 as set forth in SEQ ID NOs:7, 8, and 9, respectively, or conservative sequence modifications thereof, and light chain variable region CDR1, CDR2 and CDR3 as set forth in SEQ ID NOs:10, 11, and 12, respectively, or conservative sequence modifications thereof;
- and
- c. a human IgG1 constant domain;
- and
- (ii) the anti-PD-L1 scFv comprises:
- a. heavy chain variable region CDR1, CDR2 and CDR3 as set forth in SEQ ID NOs:
- 29, 30, and 31, respectively, or conservative sequence modifications thereof, and light chain variable region CDR1, CDR2 and CDR3 as set forth in SEQ ID NOs:32, 33, and 34, respectively, or conservative sequence modifications thereof;
- b. heavy chain variable region CDR1, CDR2 and CDR3 as set forth in SEQ ID NOs:
- 35, 36, and 37, respectively, or conservative sequence modifications thereof, and light chain variable region CDR1, CDR2 and CDR3 as set forth in SEQ ID NOs:38, 39, and 40, respectively, or conservative sequence modifications thereof;
- c. heavy chain variable region CDR1, CDR2 and CDR3 as set forth in SEQ ID NOs:
- 41, 42, and 43, respectively, or conservative sequence modifications thereof, and light chain variable region CDR1, CDR2 and CDR3 as set forth in SEQ ID NOs:44, 45, and 46, respectively, or conservative sequence modifications thereof;
- d. heavy chain variable region CDR1, CDR2 and CDR3 as set forth in SEQ ID NOs:
- 47, 48, and 49, respectively, or conservative sequence modifications thereof, and light chain variable region CDR1, CDR2 and CDR3 as set forth in SEQ ID NOs:50, 51, and 52, respectively, or conservative sequence modifications thereof;
- e. heavy chain variable region CDR1, CDR2 and CDR3 as set forth in SEQ ID NOs:
- 53, 54, and 55, respectively, or conservative sequence modifications thereof, and light chain variable region CDR1, CDR2 and CDR3 as set forth in SEQ ID NOs:56, 57, and 58, respectively, or conservative sequence modifications thereof;
- or
- f. heavy chain variable region CDR1, CDR2 and CDR3 as set forth in SEQ ID NOs:
- 59, 60, and 61, respectively, or conservative sequence modifications thereof, and light chain variable region CDR1, CDR2 and CDR3 as set forth in SEQ ID NOs:62, 63, and 64, respectively, or conservative sequence modifications thereof.
A bispecific construct comprising an anti-CD27 antibody linked to an anti-PD-L1 scFv, wherein:
- (i) the anti-CD27 antibody comprises:
- a. a heavy chain variable region comprising SEQ ID NO:17 and a light chain variable region comprising SEQ ID NO:18;
- or
- b. a heavy chain variable region comprising SEQ ID NO:19 and a light chain variable region comprising SEQ ID NO:20;
- and
- c. a human IgG1 constant domain;
- and
- (ii) the anti-PD-L1 scFv comprises:
- a. a heavy chain variable region comprising SEQ ID NO:77 and a light chain variable region comprising SEQ ID NO:78;
- b. a heavy chain variable region comprising SEQ ID NO:79 and a light chain variable region comprising SEQ ID NO:80;
- c. a heavy chain variable region comprising SEQ ID NO:81 and a light chain variable region comprising SEQ ID NO:82;
- d. a heavy chain variable region comprising SEQ ID NO:83 and a light chain variable region comprising SEQ ID NO:84;
- e. a heavy chain variable region comprising SEQ ID NO:85 and a light chain variable region comprising SEQ ID NO:86;
- or
- f. a heavy chain variable region comprising SEQ ID NO:87 and a light chain variable region comprising SEQ ID NO:88.
A bispecific construct comprising an anti-CD27 antibody linked to an anti-PD-L1 scFv, wherein:
- (i) the anti-CD27 antibody comprises heavy chain variable region CDR1, CDR2 and CDR3 as set forth in SEQ ID NOs:7, 8, and 9, respectively, or conservative sequence modifications thereof, and light chain variable region CDR1, CDR2 and CDR3 as set forth in SEQ ID NOs:10, 11, and 12, respectively, or conservative sequence modifications thereof, and a human IgG1 constant domain;
- and
- (ii) the anti-PD-L1 scFv comprises a heavy chain variable region CDR1, CDR2 and CDR3 as set forth in SEQ ID NOs:
- 47, 48, and 49, respectively, or conservative sequence modifications thereof, and light chain variable region CDR1, CDR2 and CDR3 as set forth in SEQ ID NOs:50, 51, and 52, respectively, or conservative sequence modifications thereof.
A bispecific construct comprising an anti-CD27 antibody linked to an anti-PD-L1 scFv, wherein:
- (i) the anti-CD27 antibody comprises a heavy chain variable region comprising SEQ ID NO:19, a light chain variable region comprising SEQ ID NO:20, and a human IgG1 constant domain;
- and
- (ii) the anti-PD-L1 scFv comprises a heavy chain variable region comprising SEQ ID NO:83 and a light chain variable region comprising SEQ ID NO:84.
A bispecific construct comprising an anti-CD27 antibody linked to an anti-PD-L1 scFv, wherein:
- (i) the anti-CD27 antibody comprises heavy chain variable region CDR1, CDR2 and CDR3 as set forth in SEQ ID NOs:7, 8, and 9, respectively, or conservative sequence modifications thereof, and light chain variable region CDR1, CDR2 and CDR3 as set forth in SEQ ID NOs:10, 11, and 12, respectively, or conservative sequence modifications thereof, and a human IgG1 constant domain;
- and
- (ii) the anti-PD-L1 scFv comprises heavy chain variable region CDR1, CDR2 and CDR3 as set forth in SEQ ID NOs:59, 60, and 61, respectively, or conservative sequence modifications thereof, and light chain variable region CDR1, CDR2 and CDR3 as set forth in SEQ ID NOs:62, 63, and 64, respectively, or conservative sequence modifications thereof.
A bispecific construct comprising an anti-CD27 antibody linked to an anti-PD-L1 scFv, wherein:
- (i) the anti-CD27 antibody comprises a heavy chain variable region comprising SEQ ID NO:19, a light chain variable region comprising SEQ ID NO:20, and a human IgG1 constant domain;
- and
- (ii) the anti-PD-L1 scFv comprises a heavy chain variable region comprising SEQ ID NO:87 and a light chain variable region comprising SEQ ID NO:88.
An anti-CD27 antibody, or antigen-binding fragment thereof, wherein the antibody binds to one or more residues within amino acid residues 85-89, of the extracellular domain (ECD) of human CD27 (SEQ ID NO:
- 183).
An anti-CD27 antibody, or antigen-binding fragment thereof, wherein the antibody binds to the wildtype ECD of human CD27 (SEQ ID NO:
- 183), but does not bind to a mutated version of the wildtype ECD of human CD27 having the following amino acid substitutions:
- A85S, R87A, N88A, and G89A.
An anti-CD27 antibody, or antigen-binding fragment thereof, comprising heavy chain variable region CDR1, CDR2 and CDR3 as set forth in SEQ ID NOs:1, 2, and 3, respectively, or conservative sequence modifications thereof, and light chain variable region CDR1, CDR2 and CDR3 as set forth in SEQ ID NOs:4, 5, and 6, respectively, or conservative sequence modifications thereof.
An anti-CD27 antibody, or antigen-binding fragment thereof, comprising a heavy chain variable region comprising SEQ ID NO:17 and a light chain variable region comprising SEQ ID NO:18 or sequences at least 95% identical thereto.
An anti-CD27 antibody, or antigen-binding fragment thereof, comprising heavy chain variable region CDR1, CDR2 and CDR3 as set forth in SEQ ID NOs:7, 8, and 9, respectively, or conservative sequence modifications thereof, and light chain variable region CDR1, CDR2 and CDR3 as set forth in SEQ ID NOs:10, 11, and 12, respectively, or conservative sequence modifications thereof.
An anti-CD27 antibody, or antigen-binding fragment thereof, comprising a heavy chain variable region comprising SEQ ID NO:19 and a light chain variable region comprising SEQ ID NO:20 or sequences at least 95% identical thereto.
An anti-PD-L1 antibody, or antigen-binding fragment thereof, comprising heavy chain variable region CDR1, CDR2 and CDR3 as set forth in SEQ ID NOs:29, 30, and 31, respectively, or conservative sequence modifications thereof, and light chain variable region CDR1, CDR2 and CDR3 as set forth in SEQ ID NOs:32, 33, and 34, respectively, or conservative sequence modifications thereof.
An anti-PD-L1 antibody, or antigen-binding fragment thereof, comprising a heavy chain variable region comprising SEQ ID NO:77 and a light chain variable region comprising SEQ ID NO:78 or sequences at least 95% identical thereto.
An anti-PD-L1 antibody, or antigen-binding fragment thereof, comprising heavy chain variable region CDR1, CDR2 and CDR3 as set forth in SEQ ID NOs:35, 36, and 37, respectively, or conservative sequence modifications thereof, and light chain variable region CDR1, CDR2 and CDR3 as set forth in SEQ ID NOs:38, 39, and 40, respectively, or conservative sequence modifications thereof.
An anti-PD-L1 antibody, or antigen-binding fragment thereof, comprising a heavy chain variable region comprising SEQ ID NO:79 and a light chain variable region comprising SEQ ID NO:80 or sequences at least 95% identical thereto.
An anti-PD-L1 antibody, or antigen-binding fragment thereof, comprising heavy chain variable region CDR1, CDR2 and CDR3 as set forth in SEQ ID NOs:41, 42, and 43, respectively, or conservative sequence modifications thereof, and light chain variable region CDR1, CDR2 and CDR3 as set forth in SEQ ID NOs:44, 45, and 46, respectively, or conservative sequence modifications thereof.
An anti-PD-L1 antibody, or antigen-binding fragment thereof, comprising a heavy chain variable region comprising SEQ ID NO:81 and a light chain variable region comprising SEQ ID NO:82 or sequences at least 95% identical thereto.
An anti-PD-L1 antibody, or antigen-binding fragment thereof, comprising heavy chain variable region CDR1, CDR2 and CDR3 as set forth in SEQ ID NOs:47, 48, and 49, respectively, or conservative sequence modifications thereof, and light chain variable region CDR1, CDR2 and CDR3 as set forth in SEQ ID NOs:50, 51, and 52, respectively, or conservative sequence modifications thereof.
An anti-PD-L1 antibody, or antigen-binding fragment thereof, comprising a heavy chain variable region comprising SEQ ID NO:83 and a light chain variable region comprising SEQ ID NO:84 or sequences at least 95% identical thereto.
An anti-PD-L1 antibody, or antigen-binding fragment thereof, comprising heavy chain variable region CDR1, CDR2 and CDR3 as set forth in SEQ ID NOs:53, 54, and 55, respectively, or conservative sequence modifications thereof, and light chain variable region CDR1, CDR2 and CDR3 as set forth in SEQ ID NOs:56, 57, and 58, respectively, or conservative sequence modifications thereof.
An anti-PD-L1 antibody, or antigen-binding fragment thereof, comprising a heavy chain variable region comprising SEQ ID NO:85 and a light chain variable region comprising SEQ ID NO:86 or sequences at least 95% identical thereto.
An anti-PD-L1 antibody, or antigen-binding fragment thereof, comprising heavy chain variable region CDR1, CDR2 and CDR3 as set forth in SEQ ID NOs:59, 60, and 61, respectively, or conservative sequence modifications thereof, and light chain variable region CDR1, CDR2 and CDR3 as set forth in SEQ ID NOs:62, 63, and 64, respectively, or conservative sequence modifications thereof.
An anti-PD-L1 antibody, or antigen-binding fragment thereof, comprising a heavy chain variable region comprising SEQ ID NO:87 and a light chain variable region comprising SEQ ID NO:88 or sequences at least 95% identical thereto.
A multispecific antibody comprising an anti-PD-L1 antibody having an Fc domain wherein at least one anti-CD27 antibody binding domain is bound to the Fc domain.
A multispecific antibody comprising an anti-PD-L1 antibody having an Fc domain wherein at least one anti-CD27 scFv peptide is bound to the Fc domain.
A multispecific antibody comprising an anti-PD-L1 antibody having an Fc domain wherein an anti-CD27 scFv peptide is bound to a carboxy terminus of at least one of the antibody heavy chains.
A multispecific antibody comprising an anti-PD-L1 antibody having an Fc domain wherein an anti-CD27 scFv peptide is bound to the carboxy terminus of one of the antibody heavy chains and a further scFv peptide is bound to the carboxy terminus of the other heavy chain.
An isolated nucleic acid molecule comprising a nucleotide sequence encoding an antibody variable region, wherein the antibody variable region comprises the amino acid sequence depicted in SEQ ID NO:17, 18, 19, 20, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, or 88.
An isolated nucleic acid molecule comprising a nucleotide sequence as set forth in SEQ ID NO:25, 26, 27, 28, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, or 112.
An isolated nucleic acid molecule comprising a nucleotide sequence encoding heavy and light chain variable regions of an antibody, wherein the heavy and light chain variable regions comprise the amino acid sequences depicted in SEQ ID NOs:17 and 18, SEQ ID NOs:19 and 20, SEQ ID NOs:77 and 78, SEQ ID NOs:79 and 80, SEQ ID NOs:81 and 82, SEQ ID NOs:
- 83 and 84, SEQ ID NOs:85 and 86, or SEQ ID NOs:87 and 88, respectively.
A method for treating a condition or disease in a subject, the method comprising administering to the subject an anti-CD27 antibody, or antigen binding fragment thereof, in combination with an anti-PD-L1 antibody, or antigen binding fragment thereof, wherein:
- (i) the anti-CD27 antibody, or antigen binding fragment thereof, is selected from the group consisting of:
- a. an anti-CD27 antibody, or antigen binding fragment thereof, comprising heavy chain variable region CDR1, CDR2 and CDR3 as set forth in SEQ ID NOs:1, 2, and 3, respectively, or conservative sequence modifications thereof, and light chain variable region CDR1, CDR2 and CDR3 as set forth in SEQ ID NOs:4, 5, and 6, respectively, or conservative sequence modifications thereof, and
- b. an anti-CD27 antibody, or antigen binding fragment thereof, comprising heavy chain variable region CDR1, CDR2 and CDR3 as set forth in SEQ ID NOs:7, 8, and 9, respectively, or conservative sequence modifications thereof, and light chain variable region CDR1, CDR2 and CDR3 as set forth in SEQ ID NOs:10, 11, and 12, respectively, or conservative sequence modifications thereof;
- and
- (ii) the anti-PD-L1 antibody, or antigen binding fragment thereof, is selected from the group consisting of:
- a. an anti-PD-L1 antibody, or antigen binding fragment thereof, comprising heavy chain variable region CDR1, CDR2 and CDR3 as set forth in SEQ ID NOs:
- 29, 30, and 31, respectively, or conservative sequence modifications thereof, and light chain variable region CDR1, CDR2 and CDR3 as set forth in SEQ ID NOs:32, 33, and 34, respectively, or conservative sequence modifications thereof;
- b. an anti-PD-L1 antibody, or antigen binding fragment thereof, comprising heavy chain variable region CDR1, CDR2 and CDR3 as set forth in SEQ ID NOs:
- 35, 36, and 37, respectively, or conservative sequence modifications thereof, and light chain variable region CDR1, CDR2 and CDR3 as set forth in SEQ ID NOs:38, 39, and 40, respectively, or conservative sequence modifications thereof;
- c. an anti-PD-L1 antibody, or antigen binding fragment thereof, comprising heavy chain variable region CDR1, CDR2 and CDR3 as set forth in SEQ ID NOs:
- 41, 42, and 43, respectively, or conservative sequence modifications thereof, and light chain variable region CDR1, CDR2 and CDR3 as set forth in SEQ ID NOs:44, 45, and 46, respectively, or conservative sequence modifications thereof;
- d. an anti-PD-L1 antibody, or antigen binding fragment thereof, comprising heavy chain variable region CDR1, CDR2 and CDR3 as set forth in SEQ ID NOs:
- 47, 48, and 49, respectively, or conservative sequence modifications thereof, and light chain variable region CDR1, CDR2 and CDR3 as set forth in SEQ ID NOs:50, 51, and 52, respectively;, or conservative sequence modifications thereof
- e. anti-PD-L1 antibody, or antigen binding fragment thereof, comprising heavy chain variable region CDR1, CDR2 and CDR3 as set forth in SEQ ID NOs:
- 53, 54, and 55, respectively, or conservative sequence modifications thereof, and light chain variable region CDR1, CDR2 and CDR3 as set forth in SEQ ID NOs:56, 57, and 58, respectively, or conservative sequence modifications thereof;
- and
- f. anti-PD-L1 antibody, or antigen binding fragment thereof, comprising heavy chain variable region CDR1, CDR2 and CDR3 as set forth in SEQ ID NOs:
- 59, 60, and 61, respectively, or conservative sequence modifications thereof, and light chain variable region CDR1, CDR2 and CDR3 as set forth in SEQ ID NOs:62, 63, and 64, respectively, or conservative sequence modifications thereof.
A method for treating a condition or disease in a subject, the method comprising administering to the subject an anti-CD27 antibody, or antigen binding fragment thereof, in combination with an anti-PD-L1 antibody, or antigen binding fragment thereof, wherein:
- (i) the anti-CD27 antibody, or antigen binding fragment thereof, is selected from the group consisting of:
- a. an anti-CD27 antibody, or antigen-binding fragment thereof, comprising a heavy chain variable region comprising SEQ ID NO:17 and a light chain variable region comprising SEQ ID NO:18 and
- b. an anti-CD27 antibody, or antigen-binding fragment thereof, comprising SEQ ID NO:19 and a light chain variable region comprising SEQ ID NO:20 or sequences;
- and
- (ii) the anti-PD-L1 antibody, or antigen binding fragment thereof, is selected from the group consisting of:
- a. an anti-PD-L1 antibody, or antigen binding fragment thereof, comprising a heavy chain variable region comprising SEQ ID NO:77 and a light chain variable region comprising SEQ ID NO:78;
- b. an anti-PD-L1 antibody, or antigen binding fragment thereof, comprising a heavy chain variable region comprising SEQ ID NO:79 and a light chain variable region comprising SEQ ID NO:80;
- c. an anti-PD-L1 antibody, or antigen binding fragment thereof, comprising a heavy chain variable region comprising SEQ ID NO:81 and a light chain variable region comprising SEQ ID NO:82;
- d. an anti-PD-L1 antibody, or antigen binding fragment thereof, comprising a heavy chain variable region comprising SEQ ID NO:83 and a light chain variable region comprising SEQ ID NO:84;
- e. an anti-PD-L1 antibody, or antigen binding fragment thereof, comprising a heavy chain variable region comprising SEQ ID NO:85 and a light chain variable region comprising SEQ ID NO:86;
- and
- f. an anti-PD-L1 antibody, or antigen binding fragment thereof, comprising a heavy chain variable region comprising SEQ ID NO:87 and a light chain variable region comprising SEQ ID NO:88.
A bispecific tetravalent antibody, comprising:
- i) two IgG heavy chains;
- ii) two light chains;
- and
- iii) two single chain Fv (scFv) domains;
- wherein the two IgG heavy chains and two light chains form an IgG moiety which binds specifically human PD-L1 and wherein the two scFv domains each bind specifically to human CD27, and wherein each scFv domain is connected to the C-terminal residue of one of the IgG heavy chains by a connector sequence.
Dependencies are inferred from the claim text.