Immunology

Belantamab mafodotin:

Cancer Target Rationale

• B-cell maturation antigen (BCMA), a membrane protein expressed on malignant plasma cells in all patients with multiple myeloma, supports myeloma cell proliferation and survival.^1-4

Overview

• Belantamab mafodotin is the first BCMA-targeted antibody-drug conjugate with a humanized anti-BCMA monoclonal antibody (mAb) conjugated to the microtubule inhibitor mafodotin.^2,5
• Belantamab mafodotin specifically binds to BCMA and eliminates myeloma cells by a multimodal mechanism. Mafodotin delivered to BCMA-expressing malignant cells inhibits microtubule polymerization, resulting in immune-independent apoptosis that is accompanied by release of markers of immunogenic cell death (ICD), which may contribute to an adaptive immune response. The antibody component of belantamab mafodotin enhances antibody-dependent cellular cytotoxicity and phagocytosis (ADCC/ADCP).^2,5

References:

1. Tai Y-T, Anderson KC. Targeting B-cell maturation antigen in multiple myeloma. Immunotherapy. 2015;7(11):1187-1199.
2. Tai Y-T, Mayes PA, Acharya C, et al. Novel anti-B-cell maturation antigen antibody-drug conjugate (GSK2857916) selectively induces killing of multiple myeloma. Blood. 2014;123(20):3128-3138.
3. O’Connor BP, Raman VS, Erikson LD, et al. BCMA is essential for the survival of long-lived bone marrow plasma cells. J Exp Med. 2004;199(1):91-98.
4. Cho S-F, Anderson KC, Tai Y-T. Targeting B-cell maturation antigen (BCMA) in multiple myeloma: potential uses of BCMA-based immunotherapy. Front Immunol. 2018;9:1-15. doi:10.3389/fi mmu.2018.01821.
5. Montes de Oca R, Bhattacharya S, Vitali N, et al. The anti-BCMA antibody-drug conjugate belantamab mafodotin (GSK2857916) drives immunogenic cell death and immune-mediated anti-tumor response, and in combination with an OX40 agonist potentiates in vivo activity. Presented at: European Hematology Association (EHA) Annual Meeting; June 13-16, 2019; Amsterdam, Netherlands.

Dostarlimab

Cancer Target Rationale

• Programmed cell death protein 1 (PD-1) is an immune checkpoint molecule that interacts with the PD-1 ligands PD-L1 and PD-L2 to limit T-cell–mediated immune responses.¹
• PD-L1 is expressed by many tumor types and is linked to poor clinical outcomes in a variety of cancers.¹

Overview

• Dostarlimab is a humanized anti–PD-1 mAb that binds with high affinity to PD-1 and effectively blocks interactions with PD-L1 and PD-L2.
• Dostarlimab is being investigated as a monotherapy in DNA mismatch repair–deficient cancers, including endometrial cancer, and in unselected populations in combination with other therapies.

References:

1. Dyck L, Mills KHG. Immune checkpoints and their inhibition in cancer and infectious diseases. Eur J Immunol. 2017;47(5):765-779.

ICOS Agonist IgG4 Antibody

Cancer Target Rationale

• Activation of inducible T-cell costimulator (ICOS) supports proliferation and functional activity of effector T cells and expands memory T-cell populations, which promote durable anti-tumor responses.¹

Overview

• GSK3359609 is an IgG4 ICOS agonist antibody that is designed to enhance T-cell function and enable antitumor responses without depletion of ICOS-expressing cells.^2,3
• GSK3359609 is being actively evaluated in a number of clinical trials in solid tumors, including head and neck squamous cell carcinoma and NSCLC either as monotherapy or in combination with currently available immunomodulatory agents and anticancer therapies.

References:

1. Amatore F, Gorvel L, Olive D. Inducible Co-Stimulator (ICOS) as a potential therapeutic target for anti-cancer therapy. Expert Opin Ther Targets. 2018;22(4):343-351
2. Angevin E, Barnette MS, Bauer TM, et al. INDUCE-1: a phase I open-label study of GSK3359609, an ICOS agonist antibody, administered alone and in combination with pembrolizumab in patients with advanced solid tumors. J Clin Oncol. 2017;35(15):suppl TPS3113.
3. Brett S, Yadavilli S, Seestaller-Wehr L, et al. Nonclinical evaluation of a non-depleting, first-in-class humanized IgG4 agonist anti-ICOS antibody. Poster presented at: The European Society for Medical Oncology Annual Congress; October 19-23, 2018; Munich, Germany: Poster 1840P.

TIM-3 Antagonist Antibody (Cobolimab)

Cancer Target Rationale

• T-cell immunoglobulin and mucin domain-3 (TIM-3), is a negative regulatory checkpoint molecule that regulates T-cell exhaustion, dampens the antitumor immune response, and may promote tumor cell migration and invasion.¹

Overview

• Cobolimab is a humanized TIM-3 antagonist immunoglobulin G4 (IgG4) mAb being investigated as a monotherapy and in combination with dostarlimab and TSR-033 in advanced solid tumors, including melanoma, NSCLC, and colorectal cancer.

References:

1. Das M, Zhu C, Kuchroo VK. Tim-3 and its role in regulating anti-tumor immunity. Immunol Rev. 2017;276(1):97-111.

LAG-3 Antagonist Antibody (TSR-033)

Cancer Target Rationale

• Lymphocyte activation gene-3 (LAG-3) negatively regulates T-cell activity and, in combination with PD-1, mediates T-cell exhaustion.¹

Overview

• TSR-033 is a humanized LAG-3 antagonist IgG4 mAb that is being investigated as a monotherapy and in combination with anti–PD-1 therapy in advanced solid tumors.

References:

1. Andrews LP, Marciscano AE, Drake CG, Vignali DAA. LAG3 (CD223) as a cancer immunotherapy target. Immunol Rev. 2017;276(1):80-96.

STING Agonist (GSK3745417)

Cancer Target Rationale

• Stimulator of interferon genes (STING) is a key adapter molecule that mediates sensing of cytosolic DNA and activates T-cell–dependent tumor immunity.¹

Overview

• GSK3745417 is a synthetic STING agonist that is being investigated as a monotherapy and in combination with pembrolizumab in relapsed/refractory solid tumors.

References:

1. Corrales L, McWhirter SM, Dubensky TW Jr, Gajewski TF. The host STING pathway at the interface of cancer and immunity. J Clin Invest. 2016;126(7):2404-2411

Bintrafusp Alfa Bifunctional TGF-β “Trap”/Anti-PD-L1 Fusion Protein

Cancer Target Rationale

Overview

• Bintrafusp alfa is a bifunctional fusion protein composed of the extracellular domain of the human transforming growth factor β receptor II (TGF-βRII or TGF-β “trap") fused via a flexible linker to the C-terminus of each heavy chain of the IgG1 antibody blocking PD-L1. Bintrafusp alfa is designed to allow for targeting tumor cells via two nonredundant immunostimulatory mechanisms—the TGF-β and PD-L1 pathways.^1,2
• It is being investigated as monotherapy and in combination with other anticancer agents in various malignancies.

References:

1. Knudson KM, Hicks KC, Luo X, Chen J-Q, Schlom J, Gameiro SR. M7824, a novel bifunctional anti-PD-L1/TGF trap fusion protein, promotes anti-tumor efficacy as monotherapy and in combination with vaccine. Oncoimmunology. 2018;7(5):e1426519.
2. Lan Y, Zhang D, Xu C, et al. Enhanced preclinical antitumor activity of M7824, a bifunctional fusion protein simultaneously targeting PD-L1 and TGF-ß. Sci Transl Med. 2018;10(424):eaan5488.

OX40 Agonist Antibody (GSK3174998)

Cancer Target Rationale

• Tumor necrosis factor receptor superfamily, member 4 (OX40 [CD134]) is expressed by T cells during antigen-specific priming.¹

Overview

• GSK3174998 is a humanized immunoglobulin 1 (IgG1) OX40 agonist antibody that can enhance the proliferation and survival of CD4+ and CD8+ T cells and deplete tumor-infiltrating regulatory T cells via antibody-dependent cell cytotoxicity or phagocytosis.^1,2
• GSK3174998 is being investigated in combination with other anticancer agents in multiple tumor types

References:

1. Linch SN, McNamara MJ, Redmond WL. OX40 agonists and combination immunotherapy: putting the pedal to the metal. Front Oncol. 2015;5:34
2. Aspeslagh S, Postel-Vinay S, Rusakiewicz S, Soria JC, Zitvogel L, Marabelle A. Rationale for anti-OX40 cancer immunotherapy. Eur J Cancer. 2016;52:50-66

Belantamab Mafodotin - Anti-BCMA Immunoconjugate

Cancer Target Rationale

• Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) is involved in driving necroptosis, a proinflammatory form of cell death that may promote metastasis and suppress T-cell–driven antitumor immunity.^1,2

Overview

• GSK3145095 is a small-molecule RIPK1 inhibitor.

References:

1. Najafov A, Chen H, Yuan J. Necroptosis and cancer. Trends Cancer. 2017;3(4):294-301.
2. Seifert L, Werba G, Tiwari S, et al. The necrosome promotes pancreatic oncogenesis via CXCL1 and Mincle-induced immune suppression. Nature. 2016;532(7598):245-249.

NY-ESO-ImmTAC (IMCnyeso)

Cancer Target Rationale

• New York esophageal squamous cell carcinoma 1 (NY-ESO-1) and cancer-testis antigen 2 (LAGE-1a) are immunogenic cancer-testis antigens that can elicit humoral and cellular immune responses in cancer patients.^1,2
• NY-ESO-1 and LAGE-1a are widely expressed in diverse tumor types with restricted expression in normal tissues.¹

Overview

• NY-ESO-ImmTAC (immune mobilizing monoclonal TCR against cancer [IMCnyeso]) is a bifunctional soluble high-affinity T-cell receptor (TCR) specific for NY-ESO-1 that also engages the CD3 receptor on T cells.³
• It is being studied as a monotherapy in advanced NY-ESO-1– and/or LAGE-1a–positive cancers.

References:

1. Thomas R, Al-Khadairi G, Roelands J, et al. NY-ESO-1 based immunotherapy of cancer: current perspectives. Front Immunol. 2018;9:947.
2. Rapoport AP, Stadtmauer EA, Binder-Scholl GK, et al. NY-ESO-1–specific TCR–engineered T cells mediate sustained antigen-specific antitumor effects in myeloma. Nat Med. 2015;21(8):914-921.
3. McCormack E, Adams KJ, Hassan NJ, et al. Bi-specific TCR-anti CD3 redirected T-cell targeting of NY-ESO-1- and LAGE-1-positive tumors. Cancer Immunol Immunother. 2013;62(4):773-785.

Anti-CD96 Antibody (GSK6097608)

Cancer Target Rationale

• CD96 is an immune checkpoint protein expressed on T cells and natural killer (NK) cells in multiple tumor types.^1,2,3
• CD96 effectively competes with CD226 for binding to a shared ligand, CD155, to modulate immune responses and promote tumor cell immune evasion.^1,2,3

Overview

• GSK6097608 inhibits the binding of CD96 to CD155 and activates T cells and NK cells, which enhances antitumor activity.^1,3
• GSK6097608 is a first-in-class anti-CD96 IgG1 monoclonal antibody being investigated as a monotherapy and in combination with dostarlimab (anti-PD1 antibody) in advanced solid tumors.⁴

References:

1. Blake SJ, Stannard K, Liu J, et al. Suppression of metastases using a new lymphocyte checkpoint target for cancer immunotherapy. Cancer Discov. 2016;6(4):446-459.
2. Georgiev H, Ravens I, Papadogianni G, Bernhardt G. Coming of age: CD96 emerges as modulator of immune responses. Front Immunol. 2018;9:1072. doi:10.3389/fimmu.2018.01072.
3. Mittal D, Lepletier A, Madore J, et al. CD96 is an immune checkpoint that regulates CD8+ T-cell antitumor function. Cancer Immunol Res. 2019;7(4):559-571.
4. ClinicalTrials.gov. https://clinicaltrials.gov/. Accessed July 9, 2020.
   ^§In collaboration with 23andMe

Molibresib BET Inhibitor

Cancer Target Rationale

• Bromodomain and extraterminal (BET) proteins bind to acetylated lysines in histone tails and other nuclear proteins to regulate the epigenetic landscape.¹
• They directly regulate expression of many cancer-related genes, including c-MYC.¹

Overview

• Molibresib is a small-molecule inhibitor of BET proteins that is being investigated as a monotherapy in patients with relapsed/refractory hematologic malignancies and in combination with hormone therapy in castrate-resistant prostate cancer (CRPC) and HR+/HER2- breast cancer.²

References:

1. Pérez-Salvia M, Esteller M. Bromodomain inhibitors and cancer therapy: from structures to applications. Epigenetics. 2017;12(5):323-339.
2. Dawson M, Stein EM, Huntly BJP, et al. A phase I study of GSK525762, a selective bromodomain (BRD) and extra terminal protein (BET) inhibitor: results from part 1 of phase I/II open label single agent study in patients with acute myeloid leukemia (AML). Blood. 2017;130(suppl 1): 1377.

PRMT5 Inhibitor (GSK3326595) and Type I PRMT Inhibitor (GSK3368715)

Cancer Target Rationale

• GSK is investigating the activity of two compounds that target protein arginine methyltransferases (PRMTs).
• PRMT5 is overexpressed in multiple tumor types, including lymphoma and breast, lung, and bladder cancer, and regulates splicing, gene expression, and activation of p53.^1,2

Overview

• GSK3326595, a selective inhibitor of PRMT5, is being investigated as a monotherapy in solid tumors and in combination with other therapies in various hematologic malignancies.
• GSK3368715, a type 1 PRMT inhibitor, is being investigated in phase I trials for patients with diffuse large B-cell lymphoma and solid tumors.³

References:

1. Smith E, Zhou W, Shindiapina P, Sif S, Li C, Baiocchi RA. Recent advances in targeting protein arginine methyltransferase enzymes in cancer therapy. Expert Opin Ther Targets. 2018;22(6):527-545.
2. Poulard C, Corbo L, Le Romancer M. Protein arginine methylation/demethylation and cancer. Oncotarget. 2016;7(41):67532-67550.
3. Fedoriw A, Rajapurkar SR, O’Brien S, et al. Anti-tumor activity of the type I PRMT inhibitor, GSK3368715, synergizes with PRMT5 inhibition through MTAP loss. Cancer Cell.2019;36(1):100-114.

PI3Kβ Inhibitor (GSK2636771)

Cancer Target Rationale

• The phosphoinositide 3-kinase (PI3K)/protein kinase ß (AKT) signaling pathway plays a major role in regulating cellular process involved in cancer, including proliferation, growth, survival, and migration.^1,2
• The PI3K/AKT and phosphatase and tensin homolog (PTEN) pathways are among the most frequently mutated pathways in human cancers.²

Overview

• GSK is investigating a PI3Kß inhibitor, GSK2636771, in combination with enzalutamide, in PTEN-deficient metastatic castration-resistant prostate cancer (mCRPC).

References:

1. Faes S, Dormond O. PI3K and AKT: unfaithful partners in cancer. Int J Mol Sci. 2015;16(9):21138-21152.
2. Stark A-K, Sriskantharjah S, Hessel EM, Okkenhaug K. PI3K inhibitors in inflammation, autoimmunity and cancer. Curr Opin Pharmacol. 2015;23:82-91.

Niraparib (PARP Inhibitor)

Cancer Target Rationale

• Poly ADP ribose polymerases (PARPs) are a family of enzymes involved in many functions, including DNA repair, gene expression, cellular signaling, and base excision repairs.¹
• PARP inhibition induces cell death through synthetic lethality.¹

Overview

• Niraparib is a selective PARP1/2 inhibitor approved as monotherapy for the maintenance treatment of adult patients with recurrent ovarian, fallopian tube, or primary peritoneal cancer who are in response (complete or partial) to platinum-based chemotherapy.^2,3
• Niraparib is being investigated as a monotherapy and in combination with other anticancer agents, including dostarlimab, in breast cancer, ovarian cancer, and advanced NSCLC.

References:

1. Gupte R, Liu Z, Kraus WL. PARPs and ADP-ribosylation: recent advances linking molecular functions to biological outcomes. Genes Dev. 2017;31(2):101-1261. Gupte R, Liu Z, Kraus WL. PARPs and ADP-ribosylation: recent advances linking molecular functions to biological outcomes. Genes Dev. 2017;31(2):101-126.
2. Zejula [summary of product characteristics]. Amsterdam, Netherlands: TESARO Bio Netherlands BV; 2019.
3. ZEJULA [package insert]. Waltham, MA: TESARO, Inc; 2019.