IP Library › Granted Patent US 12,319,739
Granted Patent B2
US 12,319,739 · App. 17/259,634 · Granted Jun 3, 2025

Mesothelin and CD137 binding molecules

Inventors: Jose Munoz-Olaya (Cambridge, GB); Mihriban Tuna (Cambridge, GB); Remi Fertin (Cambridge, GB); Claire Reader (Cambridge, GB); Francisca Wollerton (Cambridge, GB); Neil Brewis (Cambridge, GB)
Assignee: INVOX PHARMA LIMITED
C07K16/2878A61K2039/505C07K2317/31C07K2317/33C07K2317/35C07K2317/40C07K2317/72C07K2317/75C07K2317/92
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Quick Facts
Patent No.
US 12,319,739
App. No.
17/259,634
Granted
Jun 3, 2025
Kind
B2
Abstract

The present invention relates to antibody molecules that bind both mesothelin (MSLN) and CD137. The antibody molecules comprise a CDR-based binding site for MSLN, and a CD137 antigen-binding site located in a constant domain of the antibody molecule. The antibody molecules find application in the treatment of cancer, for example.

Claims (100)

1. An antibody molecule that binds to mesothelin (MSLN) and CD137, comprising

(a) a complementarity determining region (CDR)-based antigen-binding site for MSLN;

wherein the CDR-based antigen-binding site comprises the VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2 and VL CDR3, defined according to the ImMunoGeneTics numbering scheme, set forth in:

(i) SEQ ID NOs 42, 33, 44, 20, 22, and 80, respectively [FS28-256-271];

(ii) SEQ ID NOs 14, 16, 27, 20, 22 and 24, respectively [FS28-024-052];

(iii) SEQ ID NOs 42, 33, 44, 20, 22, and 40, respectively [FS28-256-021];

(iv) SEQ ID NOs 42, 33, 44, 20, 22, and 37, respectively [FS28-256-012];

(v) SEQ ID NOs 50, 33, 52, 20, 22 and 40, respectively [FS28-256-023];

(vi) SEQ ID NOs 42, 33, 44, 20, 22 and 41, respectively [FS28-256-024];

(vii) SEQ ID NOs 50, 33, 52, 20, 22 and 41, respectively [FS28-256-026];

(viii) SEQ ID NOs 42, 33, 44, 20, 22, and 80, respectively [FS28-256-027];

(ix) SEQ ID NOs 38, 33, 35, 20, 22, and 40, respectively [FS28-256-001];

(x) SEQ ID NOs 38, 33, 35, 20, 22, and 41 respectively [FS28-256-005];

(xi) SEQ ID NOs 46, 33, 48, 20, 22 and 37, respectively [FS28-256-014];

(xii) SEQ ID NOs 50, 33, 52, 20, 22 and 37, respectively [FS28-256-018];

(xiii) SEQ ID NOs 31, 33, 35, 20, 22 and 37, respectively [FS28-256];

(xiv) SEQ ID NOs 14, 16, 25, 20, 22 and 24, respectively [FS28-024-051];

(xv) SEQ ID NOs 14, 16, 29, 20, 22 and 24, respectively [FS28-024-053]; or

(xvi) SEQ ID NOs 14, 16, 18, 20, 22 and 24, respectively [FS28-024]; and/or

wherein the CDR-based antigen-binding site comprises the VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2 and VL CDR3, defined according to the Kabat numbering scheme set forth in:

(i) SEQ ID NOs 43, 5, 45, 21, 23, and 80, respectively [FS28-256-271];

(ii) SEQ ID NOs 15, 17, 28, 21, 23 and 24, respectively [FS28-024-052];

(iii) SEQ ID NOs 43, 34, 45, 21, 23 and 40, respectively [FS28-256-021];

(iv) SEQ ID NOs 43, 34, 45, 21, 23 and 37, respectively [FS28-256-012];

(v) SEQ ID NOs 51, 34, 53, 21, 23 and 40, respectively [FS28-256-023];

(vi) SEQ ID NOs 43, 34, 45, 21, 23 and 41, respectively [FS28-256-024];

(vii) SEQ ID NOs 51, 34, 53, 21, 23 and 41, respectively [FS28-256-026];

(viii) SEQ ID NOs 43, 34, 45, 21, 23 and 80, respectively [FS28-256-027];

(ix) SEQ ID NOs 39, 34, 36, 21, 23 and 40, respectively [FS28-256-001];

(x) SEQ ID NOs 39, 34, 36, 21, 23 and 41, respectively [FS28-256-005];

(xi) SEQ ID NOs 47, 34, 49, 21, 23 and 37, respectively [FS28-256-014];

(xii) SEQ ID NOs 51, 34, 53, 21, 23 and 37, respectively [FS28-256-018];

(xiii) SEQ ID NOs 32, 34, 36, 21, 23 and 37, respectively [FS28-256];

(xiv) SEQ ID NOs 15, 17, 26, 21, 23 and 24, respectively [FS28-024-051];

(xv) SEQ ID NOs 15, 17, 30, 21, 23 and 24, respectively [FS28-024-053]; or

(xvi) SEQ ID NOs 15, 17, 19, 21, 23 and 24, respectively [FS28-024]; and

(b) a CD137 antigen-binding site located in a CH3 domain of the antibody molecule,

wherein the CD137 antigen-binding site comprises a first sequence and a second sequence located in the AB and EF structural loops of the CH3 domain, respectively, wherein the first and second sequence have the sequence set forth in SEQ ID NOs 10 and 11 [FS22-172-003], respectively.

2. The antibody molecule according to claim 1 , wherein the antibody molecule comprises the VH domain and the VL domain set forth in:

(i) SEQ ID NOs 177 and 76, respectively [FS28-256-271];

(ii) SEQ ID NOs 58 and 54, respectively [FS28-024-052];

(iii) SEQ ID NOs 70 and 68, respectively [FS28-256-021];

(iv) SEQ ID NOs 70 and 64, respectively [FS28-256-012];

(v) SEQ ID NOs 74 and 68, respectively [FS28-256-023];

(vi) SEQ ID NOs 70 and 78, respectively [FS28-256-024];

(vii) SEQ ID NOs 74 and 78, respectively [FS28-256-026];

(viii) SEQ ID NOs 70 and 76, respectively [FS28-256-027];

(ix) SEQ ID NOs 66 and 68, respectively [FS28-256-001];

(x) SEQ ID NOs 66 and 78, respectively [FS28-256-005];

(xi) SEQ ID NOs 72 and 64, respectively [FS28-256-014];

(xii) SEQ ID NOs 74 and 64, respectively [FS28-256-018];

(xiii) SEQ ID NOs 62 and 64, respectively [FS28-256];

(xiv) SEQ ID NOs 56 and 54, respectively [FS28-024-051];

(xv) SEQ ID NOs 60 and 54, respectively [FS28-024-053]; or

(xvi) SEQ ID NOs 12 and 54, respectively [FS28-024].

3. The antibody molecule according to claim 1 , wherein the antibody molecule comprises:

(i) the VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2 and VL CDR3, defined according to the ImMunoGeneTics numbering scheme set forth in SEQ ID NOs 42, 33, 44, 20, 22, and 80, respectively [FS28-256-271]; and/or

(ii) the VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2 and VL CDR3, defined according to the Kabat numbering scheme set forth in SEQ ID NOs 43, 5, 45, 21, 23, and 80, respectively [FS28-256-271]; and/or

(iii) the VH domain and VL domain set forth in SEQ ID NOs 177 and 76, respectively [FS28-256-271].

4. The antibody molecule according to claim 1 , wherein the antibody molecule comprises:

(i) the VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2 and VL CDR3, defined according to the ImMunoGeneTics numbering scheme set forth in SEQ ID NOS SEQ ID NOS 14, 16, 27, 20, 22 and 24, respectively [FS28-024-052]; and/or

(ii) the VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2 and VL CDR3, defined according to the Kabat numbering scheme set forth in SEQ ID NOs 15, 17, 28, 21, 23 and 24, respectively [FS28-024-052]; and/or

(iii) the VH domain and VL domain set forth in SEQ ID NOs 58 and 54, respectively [FS28-024-052].

5. The antibody molecule according to claim 1 , wherein

(i) the first sequence is located between positions 14 and 17 of the CH3 domain of the antibody molecule; and/or

(ii) wherein the second sequence is located between positions 91 and 99 of the CH3 domain of the antibody molecule; and

wherein the amino acid residue numbering is according to the IMGT numbering scheme.

6. The antibody molecule according to claim 1 , wherein the antibody molecule comprises the CH3 domain sequence set forth in SEQ ID NO: 8 [FS22-172-003].

7. The antibody molecule according to claim 1 , wherein the antibody molecule comprises the heavy chain and light chain of antibody:

(i) FS22-172-003-AA/FS28-256-271 set forth in SEQ ID NOs 3 and 84, respectively;

(ii) FS22-172-003-AA/FS28-024-052 set forth in SEQ ID NOs 102 and 85, respectively;

(iii) FS22-172-003-AA/FS28-256-021 set forth in SEQ ID NOs 125 and 82, respectively;

(iv) FS22-172-003-AA/FS28-256-012 set forth in SEQ ID NOs 125 and 116, respectively;

(v) FS22-172-003-AA/FS28-256-023 set forth in SEQ ID NOs 133 and 82,

(vi) FS22-172-003-AA/FS28-256-024 set forth in SEQ ID NOs 125 and 83, respectively;

(vii) FS22-172-003-AA/FS28-256-026 set forth in SEQ ID NOs 133 and 83, respectively;

(viii) FS22-172-003-AA/FS28-256-027 set forth in SEQ ID NOs 125 and 84, respectively;

(ix) FS22-172-003-AA/FS28-256-001 set forth in SEQ ID NOs 120 and 82, respectively;

(x) FS22-172-003-AA/FS28-256-005 set forth in SEQ ID NOs 120 and 83, respectively;

(xi) FS22-172-003-AA/FS28-256-014 set forth in SEQ ID NOs 129 and 116, respectively;

(xii) FS22-172-003-AA/FS28-256-018 set forth in SEQ ID NOs 133 and 116, respectively;

(xiii) FS22-172-003-AA/FS28-256 set forth in SEQ ID NOs 114 and 116, respectively;

(xiv) FS22-172-003-AA/FS28-024-051 set forth in SEQ ID NOs 98 and 85, respectively;

(xv) FS22-172-003-AA/FS28-024-053 set forth in SEQ ID NOs 106 and 85, respectively; or

(xvi) FS22-172-003-AA/FS28-024 set forth in SEQ ID NOs 94 and 85, respectively.

8. The antibody molecule according to claim 7 , wherein the antibody molecule comprises the heavy chain and light chain set forth in SEQ ID NOs 3 and 84, respectively [FS22-172-003-AA/FS28-256-271].

9. The antibody molecule according to claim 7 , wherein the antibody molecule comprises the heavy chain and light chain set forth in SEQ ID NOs 102 and 85, respectively [FS22-172-003-AA/FS28-024-052].

10. The antibody molecule according to claim 1 , wherein the antibody molecule does not bind to Fcγ receptors.

11. The antibody molecule according to claim 1 , wherein the antibody molecule binds to immobilised MSLN with a higher affinity than to soluble MSLN.

12. The antibody molecule according to claim 1 , wherein the antibody molecule is capable of activating CD137 on an immune cell in the presence of tumour cell-surface bound MSLN.

13. The antibody molecule according to claim 1 , wherein binding of the antibody molecule to CD137 on an immune cell and to tumour cell-surface bound MSLN causes clustering of CD137 on the immune cell.

14. A nucleic acid molecule or molecules encoding the antibody molecule according to claim 1 .

15. A vector or vectors comprising the nucleic acid molecule or molecules according to claim 14 .

16. A recombinant host cell comprising the nucleic acid molecule(s) according to claim 14 , or a vector(s) comprising the nucleic acid molecule(s) according to claim 14 .

17. A method of producing an antibody molecule comprising culturing the recombinant host cell of claim 16 under conditions for production of the antibody molecule.

18. A pharmaceutical composition comprising the antibody molecule according claim 1 and a pharmaceutically acceptable excipient.

19. A method of treating cancer in an individual comprising administering to the individual a therapeutically effective amount of the antibody molecule according to claim 1 , wherein the cancer expresses MSLN and comprises tumour infiltrating lymphocytes that express CD137.

20. The method according to claim 19 , wherein the method further comprises administering a therapeutically effective amount of a second therapeutic to the individual.

21. A method of treating cancer in an individual comprising administering to the individual a therapeutically effective amount of the antibody molecule according to claim 1 , wherein the cancer is selected from the group consisting of: ovarian cancer, pancreatic cancer, lung cancer, mesothelioma, lymphoma, head and neck cancer, colorectal cancer, breast cancer, squamous cell carcinoma, gastric cancer, endometrial cancer, and cholangiocarcinoma, wherein the cancer expresses MSLN and comprises tumour infiltrating lymphocytes that express CD137.

22. The method according to claim 21 , wherein the method further comprises administering a therapeutically effective amount of a second therapeutic to the individual.

Assignments (5)
CORRECTIVE ASSIGNMENT TO CORRECT THE ASSIGNEE ADDRESS PREVIOUSLY RECORDED AT REEL: 69596 FRAME: 370. ASSIGNOR(S) HEREBY CONFIRMS THE ASSIGNMENT . Recorded Dec 30, 2024
From: F-STAR THERAPEUTICS LIMITED
To: INVOX PHARMA LIMITED
Reel/Frame 069811/0426 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Dec 16, 2024
From: F-STAR THERAPEUTICS LIMITED
To: INVOX PHARMA LIMITED
Reel/Frame 069596/0370 →
CORRECTIVE ASSIGNMENT TO CORRECT THE ASSIGNEE FROM F-STAR BETA LIMITED TO F-STAR DELTA LIMITED PREVIOUSLY RECORDED UNDER REEL AND FRAME 055695/0955 ASSIGNOR(S) HEREBY CONFIRMS THE ASSIGNMENT. Recorded May 6, 2024
From: MUNOZ-OLAYA, JOSEPH; TUNA, MIHRIBAN; FERTIN, REMI; READER, CLAIRE; BREWIS, NEIL; WOLLERTON, FRANCISCA
To: F-STAR DELTA LIMITED
Reel/Frame 067328/0109 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Dec 13, 2021
From: F-STAR DELTA LIMITED
To: F-STAR THERAPEUTICS LIMITED
Reel/Frame 058373/0577 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Mar 24, 2021
From: MUNOZ-OLAYA, JOSE; TUNA, MIHRIBAN; FERTIN, REMI; READER, CLAIRE; WOLLERTON, FRANCISCA; BREWIS, NEIL
To: F-STAR BETA LIMITED
Reel/Frame 055695/0955 →
Priority Claims (1)
GB 1811450 · Jul 12, 2018 · national
Continuity (1)
Related Publication 20210309753A1 · Oct 7, 2021
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Lo et al., Effector-attenuating Substitutions That Maintain Antibody Stability and Reduce Toxicity in Mice. J Biol Chem. Mar. 3, 2017;292(9):3900-3908. doi: 10.1074/jbc.M116.767749. Epub Jan. 11, 2017. [cited by applicant]
Seckinger et al., Development and characterization of NILK-2301, a novel CEACAM5xCD3 κλ bispecific antibody for immunotherapy of CEACAM5-expressing cancers. J Hematol Oncol. Dec. 12, 2023;16(1):117. doi: 10.1186/s13045-… [cited by applicant]
Yap et al., Abstract TPS2652: A first-in-human phase I study of FS118, an anti-LAG-3/PD-L1 bispecific antibody in patients with solid tumors that have progressed on prior PD-1/PD-L1 therapy. Journal of Clinical Oncology… [cited by applicant]
[No Author Listed], Abstract for CHI Immuno-Oncology Summit Europe. Mar. 18-22, 2019. 1 page. PDR303. [cited by applicant]
[No Author Listed], First-in-Class bispecific antibodies for cancer immunotherapy. Presentation at Takeda. Dec. 31, 2016. 24 pages. PDR160. [cited by applicant]
[No Author Listed] F-Star Modular Bispecific Antibodies. Summary for Atlas deck. Presented at JP Morgan. Jan. 2017. 1 page. PDR159. [cited by applicant]
[No Author Listed], FS118 First in Human Study in Patients With Advanced Malignancies. Sponsored by F-star Therapeutics Limited. Clinical Trial. Retrieved from https://clinicaltrials.gov/ct2/show/NCT03440437. Feb. 22, 2… [cited by applicant]
[No Author Listed], Pipeline Overview: F-star is developing a pipeline of bispecific antibodies focused on oncology and immuno-oncology. F-Start website update. Sep. 2016. 2 pages. PDR126. [cited by applicant]
Ascierto et al., Initial efficacy of anti-lymphocyte activation gene-3 (anti-LAG-3:BMS-986016) in combination with nivolumab (nivo) in pts with melanoma (MEL) previously treated with anti-PD-1/PD-L1 therapy. J Clin Onco… [cited by applicant]
Asgarov et al., A new anti-mesothelin antibody targets selectively the membrane-associated form. MAbs. Apr. 2017;9(3):Supplementary Data. doi: 10.1080/19420862.2017.1288770. 6 pages. [cited by applicant]
Awuah et al., Reduced Shedding of Surface Mesothelin Improves Efficacy of Mesothelin-Targeting Recombinant Immunotoxins. Mol Cancer Ther. Jul. 2016;15(7):1648-55. doi: 10.1158/1535-7163.MCT-15-0863. Epub May 18, 2016. [cited by applicant]
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Bernett et al., Abstract P122: Multiple bispecific checkpoint combinations enhance T cell activity. J Immunother Cancer. 2016;4(Suppl 1):P122. 2 pages. [cited by applicant]
Bernett et al., Multiple bispecific checkpoint combinations enhance T cell activity. Xencor Poster Presentation. 2016. 1 page. [cited by applicant]
Bodhankar et al., PD-L1 Monoclonal Antibody Treats Ischemic Stroke by Controlling Central Nervous System Inflammation. Stroke. Oct. 2015;46(10):2926-34. doi: 10.1161/STROKEAHA.115.010592. Epub Aug. 25, 2015. [cited by applicant]
Borlak et al., Immune-mediated liver injury of the cancer therapeutic antibody catumaxomab targeting EpCAM, CD3 and Fcγ receptors. Oncotarget. May 10, 2016;7(19):28059-74. doi: 10.18632/oncotarget.8574. [cited by applicant]
Brewis, Development of an anti-PD-L1 Fcab. Presentation. Human Antibodies and Hybrodomas Conference. Oct. 22, 2018. PDR 312. [cited by applicant]
Brewis, Identification of a PD-L1 binding Fcab: a potent inhibitor of immunosuppressive signals. Abstract. Human Antibodies and Hybridomas 2018. Jun. 11, 2018. 1 page. PDR282. [cited by applicant]
Brewis, The use of bispecific antibodies to modulate anti-tumour immune responses. Oral Presentation at ELRIG—Research and Innovation. Mar. 29, 2017. 33 pages. PDR177. [cited by applicant]
Brewis, The use of bispecific antibodies to modulate anti-tumour immune responses. Oral Presentation at Peptalk. Jan. 12, 2017. 26 pages. PDR163. [cited by applicant]
Burova et al., Abstract 1484: Combined treatment with anti-LAG-3 and anti-PD-1 fully human monoclonal antibodies inhibits tumor growth in immunocompetent double-humanized LAG-3/PD-1 mice. Proceedings: AACR 107th Annual … [cited by applicant]
Burova et al., Abstract P195: A novel anti-human LAG-3 antibody in combination with anti-human PD-1 (REGN2810) shows enhanced anti-tumor activity in PD-1 x LAG-3 dual-humanized mice and favorable pharmacokinetic and saf… [cited by applicant]
Callahan et al., Targeting T Cell Co-receptors for Cancer Therapy. Immunity. May 17, 2016;44(5):1069-78. doi: 10.1016/j.immuni.2016.04.023. [cited by applicant]
Camisaschi et al., LAG-3 expression defines a subset of CD4(+)CD25(high)Foxp3(+) regulatory T cells that are expanded at tumor sites. J Immunol. Jun. 1, 2010;184(11):6545-51. doi: 10.4049/jimmunol.0903879. Epub Apr. 26,… [cited by applicant]
Cemerski et al., T cell activation and anti-tumor efficacy of anti-LAG-3 antibodies is independent of LAG-3-MHCII blocking capacity. Poster Presentation. 30th Annual Meeting and Associated Programs of the Society for Im… [cited by applicant]
Chatterjee et al., Noninvasive Imaging of Immune Checkpoint Ligand PD-L1 in Tumors and Metastases for Guiding Immunotherapy. Mol Imaging. Jan.-Dec. 2017;16:1536012117718459. doi: 10.1177/1536012117718459. 5 pages. [cited by applicant]
Chen et al., Molecular mechanisms of T cell co-stimulation and co-inhibition. Nat Rev Immunol. Apr. 2013;13(4):227-42. doi: 10.1038/nri3405. Epub Mar. 8, 2013. Erratum in: Nat Rev Immunol. Jul. 2013;13(7):542. [cited by applicant]
Chiu et al., Antibody Structure and Function: The Basis for Engineering Therapeutics. Antibodies (Basel). Dec. 3, 2019;8(4):55. doi: 10.3390/antib8040055. [cited by applicant]
Chu et al., An Update on Anti-CD137 Antibodies in Immunotherapies for Cancer. Int J Mol Sci. Apr. 12, 2019;20(8):1822. doi: 10.3390/ijms20081822. 17 pages. [cited by applicant]
Curran et al., PD-1 and CTLA-4 combination blockade expands infiltrating T cells and reduces regulatory T and myeloid cells within B16 melanoma tumors. Proc Natl Acad Sci U S A. Mar. 2, 2010;107(9):4275-80. doi: 10.1073… [cited by applicant]
Dahlén et al., Bispecific antibodies in cancer immunotherapy. Ther Adv Vaccines Immunother. Feb. 2018;6(1):3-17. doi: 10.1177/2515135518763280. Epub Mar. 28, 2018. [cited by applicant]
Davies, Analytical challenges for next generation biologics. Oral Presentation at Waters Biopharma Mini-Seminar. May 24, 2017. 20 pages. PDR191. [cited by applicant]
Davies, Bispecific Antibodies: New Opportunities for Novel Therapies. Oral Presentation at Bioprocess UK 2016. Nov. 26, 2016. 14 pages. PDR 135. [cited by applicant]
Davies, Overcoming the Manufacturing Challenges for Bisepcific mAbs. Oral Presentation at 5th Annual Cell Culture and Bioprocessing Congress. Nov. 6, 2016. 16 pages. PDR142. [cited by applicant]
Davies, Overcoming the Manufacturing Challenges for Bisepcific mAbs. Oral Presentation at Biopronet 3rd Annual Scientific Symposium. Oct. 20, 2016. 15 pages. PDR136. [cited by applicant]
Daxini et al., Vasculitis associated with immune checkpoint inhibitors—a systematic review. Clin Rheumatol. Sep. 2018;37(9):2579-2584. doi: 10.1007/s10067-018-4177-0. Epub Jun. 19, 2018. [cited by applicant]
Del Bano et al., A Bispecific Antibody-Based Approach for Targeting Mesothelin in Triple Negative Breast Cancer. Front Immunol. Jul. 10, 2019;10:1593. doi: 10.3389/fimmu.2019.01593. [cited by applicant]
Demeure et al., T Lymphocytes infiltrating various tumour types express the MHC class II ligand lymphocyte activation gene-3 (LAG-3): role of LAG-3/MHC class II interactions in cell-cell contacts. Eur J Cancer. Sep. 200… [cited by applicant]
Deng et al., LAG-3 confers poor prognosis and its blockade reshapes antitumor response in head and neck squamous cell carcinoma. Oncoimmunology. Oct. 7, 2016;5(11):e1239005. doi: 10.1080/2162402X.2016.1239005. [cited by applicant]
Doody et al., Abstract B091: A LAG-3/PD-L1 bispecific antibody inhibits tumor growth in two syngeneic colon carcinoma models. Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science … [cited by applicant]
Doody, An anti-murine LAG-3/PD-L1 bispecific antibody which modulates T cell activity and inhibits tumour growth. Oral Presentation at 2nd Annual Advances in Immuno-Oncology Congress. May 16, 2017. 17 pages. PDR188. [cited by applicant]
Doody, In vivo Efficacy of bispecific antibodies targeting two immmune-modulatory receptors. Oral Presentation at PEGS Europe. Nov. 4, 2016. 16 pages. PDR144. [cited by applicant]
El-Khoueiry et al., The relationship of pharmacodynamics (PD) and pharmacokinetics (PK) to clinical outcomes in a phase I study of OX40 agonistic monoclonal antibody (mAb) PF-04518600 (PF-8600). J Clin Oncol. May 20, 20… [cited by applicant]
Everett et al., A LAG-3/PD-L1 bispecific antibody inhibits tumour growth in two syngeneic colon carcinoma models. Poster Presentation. AACR Tumor Immunology and Immunotherapy. Oct. 21, 2016. 1 page. PDR137. [cited by applicant]
Everett et al., Abstract PR06: A LAG-3/PD-L1 bispecific antibody inhibits tumour growth in two syngeneic colon carcinoma models. AACR Special Conference on Tumor Immunology and Immunotherapy. Oct. 20-23, 2016. Boston, M… [cited by applicant]
Everett, A LAG-3/PD-L1 Bispecific Antibody Inhibits Tumour Growth in Two Syngeneic Colon Carcinoma Models. Oral Presentation at AACR Tumor Immunology and Immunotherapy. Boston, MA. Oct. 20-23, 2016. 5 pages. PDR141. [cited by applicant]
Faroudi et al., Abstract 2399: LAG-3/PD-L1 mAb2 can overcome PD-L1-mediated compensatory upregulation of LAG-3 induced by single-agent checkpoint blockade. Proceedings: AACR Annual Meeting 2019; Mar. 29-Apr. 3, 2019. At… [cited by applicant]
Faroudi et al., Abstract B009: FS118, a LAG-3/PD-L1 bispecific antibody, capable of driving potent anti-tumour immune responses and overcome PD-(L)1-mediated compensatory. Sep. 25-28, 2019. Fifth CRI-CIMT-EATI-AACR Inte… [cited by applicant]
Faroudi et al., FS118, a LAG-3/PD-L1 bispecific antibody, capable of driving potent anti-tumour immune responses and overcome PD-(L)1-mediated compensatory. Sep. 25-28, 2019. Poster. Fifth CRI-CIMT-EATI-AACR Internation… [cited by applicant]
Fiehler, Development of an anti-PD-L1 Fcab. Presentation. European Antibody Congress. Oct. 29, 2018. 26 pages. PDR312. [cited by applicant]
Foy et al., Poxvirus-Based Active Immunotherapy with PD-1 and LAG-3 Dual Immune Checkpoint Inhibition Overcomes Compensatory Immune Regulation, Yielding Complete Tumor Regression in Mice. PLoS One. Feb. 24, 2016;11(2):e… [cited by applicant]
Frenzel et al., Phage display-derived human antibodies in clinical development and therapy. MAbs. Oct. 2016;8(7):1177-1194. doi: 10.1080/19420862.2016.1212149. Epub Jul. 14, 2016. [cited by applicant]
F-Star, First-in-Class Bispecific Antibodies for Cance Immunotherapy. Jul. 2016. Presentation. 14 pages. PDR119. [cited by applicant]
F-Star, Next-Generation Bispecifics for Cancer Immunotherapy. Feb. 2020. Presented on Mar. 11, 2020 at Immuno-Oncology Summit Europe 2020. London. 46 pages. [cited by applicant]
F-Star, Redirecting T Cells. Overcoming Cancer. Improving Lives. Oct. 2019 Presentation in Investor Meeting. 36 pages. [cited by applicant]
F-Star, Redirecting T Cells. Overcoming Cancer. Improving Lives. Apr. 2020 Presentation in Investor Meeting. 43 pages. [cited by applicant]
F-Star, Redirecting T Cells. Overcoming Cancer. Improving Lives. Jan. 2020 Presentation in Investor Meeting. 41 pages. [cited by applicant]
Gandhi et al., Expression of LAG-3 by tumor-infiltrating lymphocytes is coincident with the suppression of latent membrane antigen-specific CD8+ T-cell function in Hodgkin lymphoma patients. Blood. Oct. 1, 2006;108(7):2… [cited by applicant]
Gaspar et al., FS120 mAb2, a dual agonist bispecific antibody targeting OX40 and CD137, activates T cells in vitro and induces FcyR-independent anti-tumour activity. SITC 2018. Nov. 7, 2018. Poster. 10 pages. [cited by applicant]
Gaspar, FS120 mAb2, a dual agonist bispecific antibody targeting OX40 and CD137. SITC 2018. Nov. 11, 2018. Presentation. 12 pages. [cited by applicant]
Geuijen et al., Abstract 541: An unbiased screen identifies a CD137xPD-L1 bispecific IgG1 antibody with unique T cell activation and binding properties. Cancer Res. 2019;79(13_Supplement):541. Poster Presentation AACR C… [cited by applicant]
Gliddon, Pushing all the buttons: innovating in immuno-oncology with mAb. Oral Presentation at Phacilitate Immunotherapy World 2017. Jan. 18, 2017. 11 pages. PDR165. [cited by applicant]
Glisson et al., Phase 1 study of MEDI0562, a humanized OX40 agonist monoclonal antibody (mAb), in adult patients (pts) with advanced solid tumors. Annals Onocol. Oct. 1, 2016;27(6):vi361. doi: 10.1093/annonc/mdw378.07. [cited by applicant]
Golfier et al., Anetumab ravtansine: a novel mesothelin-targeting antibody-drug conjugate cures tumors with heterogeneous target expression favored by bystander effect. Mol Cancer Ther. Jun. 2014;13(6):1537-48. doi: 10.… [cited by applicant]
Grosso et al., Programmed death-ligand 1 (PD-L1) expression in various tumor types. J Immunother Cancer. 2013;1(Suppl 1):P53. http://www.immunotherapyofcancer.org/content/1/S1/P53. 1 page. [cited by applicant]
Gunde et al., Abstract 1532: A novel, monovalent tri-specific antibody-based molecule that simultaneously modulates PD-L1 and 4-1BB exhibits potent anti-tumoral activity in vivo. Cancer Res. 2019;79(13_Supplement):1532.… [cited by applicant]
Haines et al., Abstract 4714: Blockade of LAG-3 amplifies immune activation signatures and augments curative antitumor responses to anti-PD-1 therapy in immune competent mouse models of cancer. Proceedings: AACR Annual … [cited by applicant]
Han et al., Bispecific anti-CD3 x anti-HER2 antibody mediates T cell cytolytic activity to HER2-positive colorectal cancer in vitro and in vivo. Int J Oncol. Dec. 2014;45(6):2446-54. doi: 10.3892/ijo.2014.2663. Epub Sep… [cited by applicant]
Hassan et al., Mesothelin Immunotherapy for Cancer: Ready for Prime Time? J Clin Oncol. Dec. 2016;34(34):4171-4179. doi: 10.1200/JCO.2016.68.3672. Epub Oct. 31, 2016. [cited by applicant]
Hassan et al., Phase II clinical trial of amatuximab, a chimeric antimesothelin antibody with pemetrexed and cisplatin in advanced unresectable pleural mesothelioma. Clin Cancer Res. Dec. 1, 2014;20(23):5927-36. doi: 10… [cited by applicant]
Hebb et al., Administration of low-dose combination anti-CTLA4, anti-CD137, and anti-OX40 into murine tumor or proximal to the tumor draining lymph node induces systemic tumor regression. Cancer Immunol Immunother. Jan.… [cited by applicant]
Herbst et al., Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients. Nature. Nov. 27, 2014;515(7528):563-7. doi: 10.1038/nature14011. Author Manuscript. [cited by applicant]
Hid Cadena et al., Checks and Balances in Autoimmune Vasculitis. Front Immunol. Feb. 22, 2018;9:315. doi: 10.3389/fimmu.2018.00315. [cited by applicant]
Ho et al., A novel high-affinity human monoclonal antibody to mesothelin. Int J Cancer. May 1, 2011;128(9):2020-30. doi: 10.1002/ijc.25557. [cited by applicant]
Horn et al., CD3xPDL1 bi-specific T cell engager (BiTE) simultaneously activates T cells and NKT cells, kills PDL1+ tumor cells, and extends the survival of tumor-bearing humanized mice. Oncotarget. Aug. 3, 2017;8(35):5… [cited by applicant]
Huang et al., Abstract PR03: Combinatorial blockade of PD-1, CTLA-4, and LAG-3 pathways inhibits murine ovarian tumor growth. Abstracts: AACR Special Conference: Advances in Ovarian Cancer Research: Exploiting Vulnerabi… [cited by applicant]
Iwai et al., Involvement of PD-L1 on tumor cells in the escape from host immune system and tumor immunotherapy by PD-L1 blockade. Proc Natl Acad Sci U S A. Sep. 17, 2002;99(19):12293-7. doi: 10.1073/pnas.192461099. Epub… [cited by applicant]
Jochems et al., Analyses of functions of an anti-PD-L1/TGFBR2 bispecific fusion protein (M7824). Oncotarget. Sep. 8, 2017;8(43):75217-75231. doi: 10.18632/oncotarget.20680. [cited by applicant]
Kehry et al., Abstract 271: Targeting PD-1, TIM-3 and LAG-3 in combination for improved immunotherapy combinations. AACR 106th Annual Meeting. Apr. 18-22, 2015. Philadelphia, PA. doi: 10.1158/1538-7445.AM2015-271. 8 pag… [cited by applicant]
Klooster et al., Abstract B088: Generation of immuno-modulatory receptor binding bispecific antibodies to modulate tumor immunity. Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Sci… [cited by applicant]
Koopmans et al., A novel bispecific antibody for EGFR-directed blockade of the PD-1/PD-L1 immune checkpoint. Oncoimmunology. May 31, 2018;7(8):e1466016. doi: 10.1080/2162402X.2018.1466016. [cited by applicant]
Kraman et al., A LAG-3/PD-L1 bispecific antibody inhibits tmour growth in two syngeneic colon carcinoma models. Poster Presentation. BSI/NVVI Congress. Dec. 6, 2016. 1 page. PDR153. [cited by applicant]
Kraman et al., A LAG-3/PD-L1 bispecific antibody inhibits tumour growth in two syngeneic colon carcinoma models. Abstract B091. Poster Presentation. CRI-CIMT-EATI-AACR Cancer Immunotherapy Conference. Sep. 26, 2016. 1 p… [cited by applicant]
Kraman et al., A LAG-3/PD-L1 bispecific antibody inhibits tumour growth in two syngeneic colon carcinoma models. Poster 003. Poster Presentation. 2nd Annual Advances in Immuno-Oncology Congress. May 15, 2017. 1 page. PD… [cited by applicant]
Kraman et al., A LAG-3/PD-L1 bispecific antibody inhibits tumour growth in two syngeneic colon carcinoma models. Poster 1103. Poster Presentation. Keystone Symposium—Cancer Immunology and Immunotherapy. Mar. 19, 2017. 1… [cited by applicant]
Kraman et al., A LAG-3/PD-L1 bispecific antibody inhibits tumour growth in two syngeneic colon carcinoma models. Poster 128. Poster Presentation at SITC. Nov. 9, 2016. 1 page. PDR143. [cited by applicant]
Kraman et al., A LAG-3/PD-L1 bispecific antibody inhibits tumour growth in two syngeneic colon carcinoma models. Poster 5651. Poster Presentation. AACR Annual Meeting. Apr. 1, 2017. 1 page. PDR176. [cited by applicant]
Kraman et al., A Lag-3/PD-L1 bispecific antibody inhibits tumour growth in two syngeneic colon carcinoma models. Poster Presentation. International Conference on Human & Translational Immunology. Sep. 16, 2016. 1 page. … [cited by applicant]
Kraman et al., A LAG-3/PD-L1 bispecific antibody inhibits tumour growth in two syngeneic coon carcinoma models. Poster 3005. Poster Presentation. Keystome Symposium—Biobetters and Next-Generation Biologics. Jan. 22-26, … [cited by applicant]
Kraman et al., Abstract 5651:A LAG-3/PD/L1 bispecific antibody inhibits tumor growth in two syngeneic colon carcinoma models. AACR Annual Meeting 2017. Apr. 1-5, 2017. Washington, DC. Doi: 10.1158/1538-7445.AM2017-5651.… [cited by applicant]
Kraman et al., Dual blockade of PD-L1 and LAG-3 with FS118, a unique bispecific antibody, induces CD8+ T-cell activation and modulates the tumour microenvironment to promote anti-tumour immune responses. Apr. 14-18, 201… [cited by applicant]
Kraman et al., Dual blockade of PD-L1 and LAG-3 with FS118, a unique bispecific antibody, induces T-cell activation with the potential to drive potent anti-tumour immune responses. Nov. 7, 2017;5 Suppl 2 (87):Abstract P… [cited by applicant]
Kraman et al., Dual blockade of PD-L1 and LAG-3 with FS118, a unique bispecific antibody, induces T-cell activation with the potential to drive potent anti-tumour immune responses. Apr. 14-18, 2018;78(13 Suppl);Abstract… [cited by applicant]
Kraman et al., Dual blockade of PD-L1 and LAG-3 with FS118, a unique bispecific antibody, induces T-cell activation with the potential to drive potent anti-tumour immune responses. Poster P348. 32nd Annual Meeting and P… [cited by applicant]
Kraman et al., FS118, a Bispecific Antibody Targeting LAG-3 and PD-L1, Enhances T-Cell Activation Resulting in Potent Antitumor Activity. Clin Cancer Res. Jul. 1, 2020;26(13):3333-3344. doi: 10.1158/1078-0432.CCR-19-354… [cited by applicant]
Kunik et al., Structural consensus among antibodies defines the antigen binding site. PLoS Comput Biol. 2012;8(2):e1002388. doi: 10.1371/journal.pcbi.1002388. Epub Feb. 23, 2012. 12 pages. [cited by applicant]
Kvarnhammar et al., The CTLA-4 x OX40 bispecific antibody ATOR-1015 induces anti-tumor effects through tumor-directed immune activation. J Immunother Cancer. Apr. 11, 2019;7(1):103. doi: 10.1186/s40425-019-0570-8. [cited by applicant]
La Motte-Mohs et al., Abstract 3217: MGD013, a bispecific PD-1 x LAG-3 Dual-Affinity Re-Targeting (DART®) protein with T-cell immunomodulatory activity for cancer treatment. AACR 107th Annual Meeting. Apr. 16-20, 2016. … [cited by applicant]
La Motte-Mohs et al., MGD013, a bispecific PD-1 x LAG-3 Dual-Affinity Re-Targeting (DART®) protein with T-cell immunomodulatory activity for cancer treatment. Poster Presentation. 2016. http://ir.macrogenics.com/events.… [cited by applicant]
Lakins et al., FS222 mAb2, a bispecific conditional agonist antibody targeting CD137 and PD-L1, induces potent lymphocyte activation and has a favourable safety profile. F-star, Cambridge, UK. Poster Presentation. AACR … [cited by applicant]
Lakins et al., Optimising TNFRSF agonism and checkpoint blockade with a novel CD137/PD-L1 bispecific antibody. Abstracts Therapeutic Development. Dec. 1, 2018;29(Supplement 10):X30. doi: 10.1093/annonc/mdy487.014. 1 pag… [cited by applicant]
Lamberts et al., ImmunoPET with Anti-Mesothelin Antibody in Patients with Pancreatic and Ovarian Cancer before Anti-Mesothelin Antibody-Drug Conjugate Treatment. Clin Cancer Res. Apr. 1, 2016;22(7):1642-52. doi: 10.1158… [cited by applicant]
Larkin et al., Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma. N Engl J Med. Jul. 2, 2015;373(1):23-34. doi: 10.1056/NEJMoa1504030. Epub May 31, 2015. Erratum in: N Engl J Med. Nov. 29, 2018;379(… [cited by applicant]
Levitan, Amgen Halts Rilotumumab Development Due to Increased Death Signal. Cancer Network. Nov. 26, 2014. Retrieved from www.cancernetwork.com/view/amgen-halts-rilotumumab-development-due-increased-death-signal. 3 page… [cited by applicant]
Li et al., Discovery and preclinical characterization of the antagonist anti-PD-L1 monoclonal antibody LY3300054. J Immunother Cancer. Apr. 30, 2018;6(1):31. doi: 10.1186/s40425-018-0329-7. Erratum in: J Immunother Canc… [cited by applicant]
Lin et al., Fc-dependent expression of CD137 on human NK cells: insights into “agonistic” effects of anti-CD137 monoclonal antibodies. Blood. Aug. 1, 2008;112(3):699-707. doi: 10.1182/blood-2007-11-122465. Epub Jun. 2, … [cited by applicant]
Link et al., Abstract 3752: Preclinical pharmacology of MP0310: A 4-1BB/FAP bispecific DARPin drug candidate promoting tumor-restricted T-cell costimulation. Cancer Res. Jul. 1, 2018;78(13_Supplement):3752. [cited by applicant]
Liu et al., Abstract 3642: Tumor-antigen expression-dependent activation of the CD137 costimulatory pathway by bispecific DART® proteins. Cancer Res. Jul. 1, 2017;77(13_Supplement):3642. [cited by applicant]
Liu et al., Dual Targeting of Innate and Adaptive Checkpoints on Tumor Cells Limits Immune Evasion. Cell Rep. Aug. 21, 2018;24(8):2101-2111. doi: 10.1016/j.celrep.2018.07.062. [cited by applicant]
Ma et al., Recognition of mesothelin by the therapeutic antibody MORAb-009: structural and mechanistic insights. J Biol Chem. Sep. 28, 2012;287(40):33123-31. doi: 10.1074/jbc.M112.381756. Epub Jul. 11, 2012. [cited by applicant]
Mayes et al., Abstract 539: A bispecific Fc-silenced IgG1 antibody (MCLA-145) requires PD-L1 binding to activate CD137. Cancer Res. 2019;79(13_Supplement):539. AACR Presentation 2019. Jul. 1, 2019. doi: 10.1158/1538-744… [cited by applicant]
McCourt et al., KY1055; a novel ICOS/PD-L1 bispecific antibody, enhance T cell activation and delivers potent monotherapy anti-tumour response in vivo. Abstract. CIMT 2018. Feb. 28, 2018. 1 page. PDR245. [cited by applicant]
McCourt et al., KY1055; a novel ICOS/PD-L1 bispecific antibody, enhance T cell activation and delivers potent monotherapy anti-tumour response in vivo. Poster Presentation. CIMT Conference. May 9, 2018. 1 page. PDR 264. [cited by applicant]
McCourt et al., KY1055; a novel ICOS/PD-L1 bispecific antibody, enhance T cell activation and delivers potent monotherapy anti-tumour response in vivo. Presentation. CIMT Conference. May 9, 2018. 13 pages. PDR265. [cited by applicant]
McCourt, Development of an ICOS/PD-L1 Bispecific, Mar. 18-22, 2019. Abstract. Cambridge Healthtech Institute's 4th Annual Immuno-Oncology Summit Europe 2019 (London). [cited by applicant]
Melero et al., Clinical development of immunostimulatory monoclonal antibodies and opportunities for combination. Clin Cancer Res. Mar. 1, 2013;19(5):997-1008. doi: 10.1158/1078-0432.CCR-12-2214. [cited by applicant]
Michaelson et al., Anti-tumor activity of stability-engineered IgG-like bispecific antibodies targeting Trail-R2 and LTbetaR. MAbs. Mar.-Apr. 2009;1(2):128-41. doi: 10.4161/mabs.1.2.7631. Epub Mar. 11, 2009. [cited by applicant]
Munoz-Olaya, Development of an anti-PD-L1Fcab. Presentation. PEGS Lisbon. Nov. 16, 2018. 24 pages. PDR321. [cited by applicant]
Nalivaiko et al., A Recombinant Bispecific CD20xCD95 Antibody With Superior Activity Against Normal and Malignant B-cells. Mol Ther. Feb. 2016;24(2):298-305. doi: 10.1038/mt.2015.209. Epub Nov. 19, 2015. [cited by applicant]
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