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Investigational drugs mentioned are for use in clinical studies only, and may be studied alone or in combination with drugs for indications that have not been approved by the FDA. Approved drugs mentioned are also being studied for uses for which they are not approved. Safety and efficacy have not been established for any of these drugs for the uses being studied.
AbbVie in no way intends to recommend or imply that these drugs should be used for unapproved uses.
Acute Myeloid Leukemia (AML) Approved
Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL) Approved
Mantle Cell Lymphoma (MCL)*
Multiple Myeloma (MM)
Myelodysplastic Syndromes (MDS)
Diffuse Large B-Cell Lymphoma (DLBCL)**
*Sponsored by Pharmacyclics
**Sponsored by Genentech/Roche
OVERVIEW
Navitoclax (ABT-263) is an orally active dual inhibitor of the antiapoptotic proteins, BCL-XL and BCL-2.1
PROPOSED MECHANISM OF ACTION
The BCL-2 family comprises 2 broad categories of pro-survival (BCL-2, BCL-XL, BCL-w, MCL-1, and A1) and pro-apoptotic (Bax, Bak, Bim, Bid, Puma, Bad, Noxa, Bik, Bmf, and Hrk) proteins. Generally, the balance between these proteins determines whether a cell lives or dies (i.e. apoptosis). Navitoclax has been shown to exhibit single-agent activity in tumors dependent on Bcl-2 or Bcl-XL for survival.2
However, the expression of MCL-1 is a possible escape mechanism which may allow for resistance to navitoclax.2 Therefore, in JAK signaling-dependent malignancies, inhibiting the JAK2 signaling network at two nodal points, both the initiating stage (JAK2) and the effector stage (BCL-XL/BCL-2) may reduce tumor burden while minimizing resistance.5,6 Furthermore, in preclinical studies, navitoclax-induced cell death is enhanced by JAK inhibitors, which increase BCL-XL dependence. Combined targeting of JAK2 and BCL-2/BCL-XL was shown to be able to circumvent and overcome acquired resistance to single-agent JAK2 inhibitor treatment in preclinical models.6
DEVELOPMENT
Navitoclax is in clinical development for myelofibrosis in combination with ruxolitinib, for myeloproliferative neoplasms with or without ruxolitinib.
CLINICAL TRIALS
View select clinical trials with navitoclax now. To view a full list of clinical trials in which navitoclax is being investigated, please visit ClinicalTrials.gov.
Navitoclax (ABT-263) is an unapproved investigational drug under clinical development. Safety and efficacy have not been established.
- Tse C, et al. ABT-263: a potent and orally bioavailable Bcl-2 family inhibitor. Cancer Res. 2008;68(9):3421-3428.
- Chen J, et al. The Bcl-2/Bcl-XL/Bcl-w Inhibitor, Navitoclax, Enhances the Activity of Chemotherapeutic Agents In Vitro and In Vivo. Mol Cancer Ther . 2011;10(12):2340-2349.
- Alexander T, et al. ASCO Annual Meeting 2018. TPS10575 Journal of Clinical Oncology 36, no. 15_suppl.
- Khaw et al. Venetoclax responses of pediatric ALL xenografts reveal sensitivity of MLL-rearranged leukemia. Blood. 2016;128:1382-95.
- Waibel M, et al. Combined Targeting of JAK2 and Bcl-2/Bcl-xL to Cure Mutant JAK2-Driven Malignancies and Overcome Acquired Resistance to JAK2 Inhibitors. Cell Rep. 2013;5(4):1047-1059.
- Zhang M, et al. Selective targeting of JAK/STAT signaling is potentiated by Bcl-xL blockade in IL-2–dependent adult T-cell leukemia. Proc Natl Acad Sci U S A. 2015;112(40):12480-12485.
Navitoclax Proposed MOA in Myelofibrosis
View the role of BCL-XL in myelofibrosis and learn about navitoclax and its role in BCL-XL inhibition.
Related Links
OVERVIEW
Eftozanermin alfa (ABBV-621) is a Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand (TRAIL) receptor agonist in early phase clinical development.
PROPOSED MECHANISM OF ACTION1,2
TRAIL is a member of the tumor necrosis factor (TNF) superfamily of proteins that play diverse roles in the activation of several intracellular signaling pathways that control cell proliferation, survival, and apoptosis.
(Adapted from Goncharenko-Khaider N, et al. (February 27th 2013), IntechOpen, DOI: 10.5772/53380. http://creativecommons.org/licenses/by/3.0/ for CC BY 3.0)
Eftozanermin alfa induces apoptosis via the extrinsic apoptotic pathway by binding to the TRAIL death receptor. Eftozanermin alfa exhibits potent antitumor activity in vivo as a monotherapy or in combination with targeted agents and/or chemotherapy using solid tumor or hematologic xenograft tumors.
The combination of eftozanermin alfa and BCL-2 inhibitor venetoclax may overcome resistance to TRAIL anti-cancer therapeutics in hematologic malignancies with elevated expression of the anti-apoptotic proteins in the BCL-2 family.
DEVELOPMENT
Eftozanermin alfa is being investigated in Phase 1 trial in combination with bortezomib plus dexamethasone for the treatment of relapsed/refractory multiple myeloma.
CLINICAL TRIALS
View select clinical trials with eftozanermin alfa now. To view a full list of clinical trials in which eftozanermin alfa is being investigated, please visit ClinicalTrials.gov.
Eftozanermin alfa is an unapproved investigational drug under clinical development. Safety and efficacy have not been established.
- Morgan-Lappe SE. ABBV-621: A best-in-class TRAIL-receptor agonist fusion protein that enhances optimal clustering for the treatment of solid and hematologic tumors. Abstract #DDT01-03. AACR Annual Meeting; April 1-5, 2017; Washington, DC.
- Tahir SK, et al. Abbv-621 Is a Novel and Potent TRAIL Receptor Agonist Fusion Protein That Induces Apoptosis Alone and in Combination with Navitoclax and Venetoclax in Hematological Tumors. Blood. 2017 130:2812.
Related Links
Multiple Myeloma (MM)
OVERVIEW
ABBV-383 (previously known as TNB-383) is a fully-human CD3 x BCMA bispecific antibody that is in development to treat multiple myeloma.
PROPOSED MECHANISM OF ACTION
BCMA (B cell maturation antigen) is exclusively expressed on the surface of plasmablasts and differentiated plasma cells (PCs), but not on memory B cells, naïve B cells, CD34+ hematopoietic stem cells, and other normal tissue cells. BCMA supports survival of long-lived PCs, production of antibodies and immunoglobulin class switching.1
Multiple myeloma is characterized by the expansion of malignant PCs in the bone marrow (BM), associated with excessive production of monoclonal immunoglobulins. In MM, expression of BCMA is significantly increased on malignant vs normal PCs and overexpression of BCMA promotes proliferation and survival of MM cells.1
ABBV-383 is designed with a set of unique features including an αCD3 moiety that allows lysis with minimal cytokine release, two αBCMA domains for high-affinity cell surface BCMA binding, and a silenced IgG4 backbone preventing nonspecific immune activation and permits longer interval dosing.2-4
DEVELOPMENT
ABBV-383 is a is being investigated in a phase 1 trial to treat R/R MM.
CLINICAL TRIALS
View select clinical trials with ABBV-383 now. To view a full list of clinical trials in which ABBV-383 is being investigated, please visit ClinicalTrials.gov.
ABBV-383 is an unapproved investigational drug under clinical development. Safety and efficacy have not been established.
- Cho SF, Anderson KC, Tai YT. Targeting B cell maturation antigen (BCMA) in multiple myeloma: potential uses of BCMA-based immunotherapy. Frontiers in immunology. 2018 Aug 10;9:1821.
- Foureau DM, et al. Ex vivo efficacy of BCMA-bispecific antibody TNB-383B in relapsed/refractory multiple myeloma. eJHaem. 2020;1:113–121.
- Buelow B, et al. Development of a fully human T-cell engaging bispecific antibody for the treatment of multiple myeloma. ASCO Annual Meeting. 2018.
- Buelow B, et al. T Cell Engagement without Cytokine Storm: A Novel Bcma x CD3 Antibody Killing Myeloma Cells with Minimal Cytokine Secretion. Blood. 2017;130(Suppl_1):501.
Related Links
Multiple Myeloma (MM)
OVERVIEW
Telisotuzumab vedotin (Teliso-V; ABBV-399) is a c-Met-targeted antibody-drug conjugate (ADC) comprised of the ABT-700 (c-Met-targeting) antibody conjugated to the cytotoxic microtubule inhibitor monomethylauristatin E (MMAE) via a cleavable valine–citrulline (vc) linker.
PROPOSED MECHANISM OF ACTION
The c-Met receptor tyrosine kinase is the cell surface receptor for hepatocyte growth factor (HGF) encoded by the MET protooncogene. MET is aberrantly activated in cancers contributing to tumor progression, angiogenesis, invasiveness, metastasis, and resistance and is overexpressed in non-small cell lung cancer (NSCLC; 40%) and several other solid tumor types.1
Prior c-Met inhibitors require MET amplification and/or c-Met activation for activity; however, as demonstrated in preclinical models, Teliso-V uses c-Met to deliver a cytotoxin to c-Met-overexpressing tumor cells enabling cell killing regardless of reliance on MET signaling.1 Although, MET amplification is a therapeutically actionable target, it generally occurs in 1% to 5% of de novo cancers, whereas c-Met overexpression is more common, occurring in up to 50% of many advanced solid tumors.2
The use of an ADC that targets c-Met–positive tumors represents a therapeutic strategy with which to induce tumor cell killing independently of MET signaling pathway inhibition because it involves the delivery of the potent cytotoxin MMAE directly to c-Met–positive tumor cells.2
Although a c-Met–targeting ADC may present the risk of on target toxicity based on c-Met normal tissue expression, preclinical and early phase results have demonstrated a strong correlation between Teliso-V anti-tumor activity and c-Met expression levels as c-Met expression is significantly higher in many cancers compared with normal tissue.1
DEVELOPMENT
Teliso-V is in phase 3 development in patients with previously treated c-Met+ non-small cell lung cancer (NSCLC).
CLINICAL TRIALS
View select clinical trials with telisotuzumab vedotin now. To view a full list of clinical trials in which telisotuzumab vedotin is being investigated, please visit ClinicalTrials.gov.
Telisotuzumab vedotin is an unapproved investigational drug under clinical development. Safety and efficacy have not been established.
- Wang J, Anderson MG, Oleksijew A, et al. ABBV-399, a c-Met antibody-drug conjugate that targets both MET-amplified and c-Met-overexpressing tumors, irrespective of MET pathway dependence. Clin Cancer Res. 2017 Feb 15;23(4):992-1000.
- Strickler JH, et al. First-in-Human Phase I, Dose-Escalation and -Expansion Study of Telisotuzumab Vedotin, an Antibody–Drug Conjugate Targeting c-Met, in Patients With Advanced Solid Tumors. Journal of Clinical Oncology . 2018;36(33):3298-3306.
Telisotuzumab vedotin (Teliso-V; ABBV-399) – c-Met-Targeted ADC
Related Links
c-Met+ Non Small Cell Lung Cancer (NSCLC)
OVERVIEW
ABBV-400 is a c-Met targeting antibody-drug conjugate (ADC) employing a topoisomerase inhibitor that is being investigated in non-small cell lung cancer (NSCLC) and gastroesophageal adenocarcinoma (GEA).
PROPOSED MECHANISM OF ACTION
The protein, mesenchymal-epithelial transition factor (c-Met), which is also known as Met, AUTS9, RCCP2, DFNB97 and hepatocyte growth factor receptor (HGFR), is essential for survival and function of normal cells.1
In numerous cancers, the MET gene, which encodes the protein c-Met, is either amplified or mutated to constantly activate its downstream signaling pathways to sustain rapid proliferation and survival of cancer cells. In NSCLC, both c-Met and HGF are over-expressed relative to the adjacent normal lung tissues.1
c-Met antibodies bind c-Met receptors, which are internalized and cytotoxins attached to the antibody via linkers are released into the cytosol where they seek to damage cancerous cells.
ABBV-400 uses c-Met to deliver a topoisomerase inhibitor to overexpressing tumor cells inhibiting DNA replication thus stopping cell proliferation and inducing cytotoxicity.
DEVELOPMENT
ABBV-400 is being investigated to treat non-small cell lung cancer (NSCLC) and gastroesophageal adenocarcinoma (GEA).
CLINICAL TRIALS
View select clinical trials with ABBV-400 now. To view a full list of clinical trials in which ABBV-400 is being investigated, please visit ClinicalTrials.gov.
ABBV-400 is an unapproved investigational drug under clinical development. Safety and efficacy have not been established.
- Park KC, Richardson DR. The c-MET oncoprotein: Function, mechanisms of degradation and its targeting by novel anti-cancer agents. Biochimica et Biophysica Acta (BBA)-General Subjects. 2020 Oct 1;1864(10):129650.
Related Links
Non-Small Cell Lung Cancer (NSCLC)
Gastroesophageal Adenocarcinoma (GEA)
OVERVIEW
ABBV-514 is in development for the treatment of non-small cell lung cancer (NSCLC) and head and neck squamous cell carcinoma (HNSCC) as a single agent and in combination with a PD-1 inhibitor.
DEVELOPMENT
ABBV-514 is being investigated in a Phase 1 trial for the treatment of NSCLC and HNSCC.
CLINICAL TRIALS
View select clinical trials with ABBV-514 now. To view a full list of clinical trials in which ABBV-514 is being investigated, please visit ClinicalTrials.gov.
ABBV-514 is an unapproved investigational drug under clinical development. Safety and efficacy have not been established.
Related Links
Non-Small Cell Lung Cancer (NSCLC) and Head and Neck Squamous Cell Carcinoma (HNSCC)
OVERVIEW
Cofetuzumab pelidotin (ABBV-647) is a PTK7-targeted antibody-drug conjugate (ADC).
PROPOSED MECHANISM OF ACTION1
Cofetuzumab pelidotin binds PTK7, a highly conserved but catalytically inactive receptor tyrosine kinase in the Wnt signaling pathway. PTK7 is enriched on tumor initiating cells (TICs) in at least three tumor types (Triple negative breast cancer [TNBC], non-small cell lung cancer [NSCLC], and ovarian cancer) and has increased expression in tumors versus normal tissues.
DEVELOPMENT
Cofetuzumab pelidotin is being investigated in a phase 1 study for the treatment of patients with non-small cell lung cancer.
CLINICAL TRIALS
View select clinical trials with cofetuzumab pelidotin now. To view a full list of clinical trials in which cofetuzumab pelidotin is being investigated, please visit ClinicalTrials.gov.
Cofetuzumab pelidotin is an unapproved investigational drug under clinical development. Safety and efficacy have not been established.
- Damelin M, et al. A PTK7-targeted antibody-drug conjugate reduces tumor-initiating cells and induces sustained tumor regressions. Sci Transl Med. 2017;9(372):eaag2611.
Related Links
Non-Small Cell Lung Cancer (NSCLC)
OVERVIEW
ABBV-011 is a SEZ6-targeted antibody-drug conjugate (ADC) with a calicheamicin payload being investigated in SCLC.
PROPOSED MECHANISM OF ACTION
Seizure-related homolog 6 (SEZ6) is a transmembrane protein found on the cell surface of select neuronal lineage cells.1,2
SEZ6 is selectively expressed on neuroendocrine tumors, including SCLC.3 SEZ6 was chosen as a target for the development of novel ADCs carrying payloads designed to kill neuroendocrine tumor cells, and thereby treat patients with such tumors.4
- Using a bioinformatic approach, RNA expression analysis and immunohistochemistry identified SEZ6 as a highly expressed surface marker in neuroendocrine tumors including SCLC, with limited expression in normal tissue.
- ABBV-011 comprises a SEZ6-binding antibody that induces rapid receptor internalization, and is suitable for carrying a tumor cell-killing payload.
- ABBV-011 uses a calicheamicin payload to target SEZ6-bearing tumor cells. The calicheamicins are a family of enediyne antibiotics that exhibit extraordinary activity against murine tumors, such as leukemia and solid neoplasms. The calicheamicins are profoundly potent sequence specific, double strand DNA-cleaving agents.5
- Conjugation of the SEZ6-targeting antibody to a novel calicheamicin linker-drug resulted in ABBV-011, a potent ADC targeting SEZ6-expressing tumor cells.
DEVELOPMENT
ABBV-011 is being investigated in a Phase 1 trial for the treatment of SCLC.
CLINICAL TRIALS
View select clinical trials with ABBV-011 now. To view a full list of clinical trials in which ABBV-011 is being investigated, please visit ClinicalTrials.gov.
ABBV-011 is an unapproved investigational drug under clinical development. Safety and efficacy have not been established.
- Shimizu-Nishikawa K, et al. Cloning and characterization of seizure-related gene, SEZ-6. Biochem Biophys Res Commun. 1995;216(1):382-9.
- Gunnersen JM, et al. Sez-6 proteins affect dendritic arborization patterns and excitability of cortical pyramidal neurons. Neuron. 2007;56(4):621-39.
- Kudoh S, et al. Significance of achaete-scute complex homologue 1 (ASCL1) in pulmonary neuroendocrine carcinomas; RNA sequence analyses using small cell lung cancer cells and Ascl1-induced pulmonary neuroendocrine carcinoma cells. Histochem Cell Biol. 2020;153(6):443-456.
- Wiedemeyer WR et al. ABBV-011, A Novel, Calicheamicin-Based Antibody–Drug Conjugate, Targets SEZ6 to Eradicate Small Cell Lung Cancer Tumors. Mol Cancer Ther. 2022;21:986-98.
- Grediĉak M, Jerić I. Enediyne compounds-new promises in anticancer therapy. Acta Pharmaceutica. 2007;57(2):133-50.
Related Links
Small Cell Lung Cancer (SCLC)
OVERVIEW
Veliparib (ABT-888) is a potent orally bioavailable poly (adenosine diphosphate [ADP]-ribose) polymerase (PARP) small molecule inhibitor in clinical development.1,2
PROPOSED MECHANISM OF ACTION
Proteins of the PARP family are naturally occurring enzymes in human cells that are critical to the repair of single-strand DNA breaks.1,2 While this is a useful process to maintain the integrity of healthy cells, the same process can also repair chemotherapy-induced DNA damage in cancer cells that may have limited capacity for repairing double-strand DNA breaks.1,2
Veliparib is designed to inhibit PARP1 and PARP2, potentially leading to the accumulation of single-strand and double-strand DNA breaks in tumor cells that may have limited capacity for DNA repair, which results in chromosomal instability, cell cycle arrest, and subsequent apoptosis.1,2,3 Veliparib therefore may enhance the activity of multiple DNA-damaging chemotherapeutic and targeted agents.
DEVELOPMENT
Veliparib is being developed in settings where it can be combined with common DNA-damaging therapies like chemotherapy or radiation.1,2,4-7 It is in phase 3 development in combination with chemotherapies for breast cancer, high-grade epithelial ovarian, fallopian tube, or primary peritoneal cancer.
CLINICAL TRIALS
View select clinical trials with veliparib now. To view a full list of clinical trials in which veliparib is being investigated, please visit ClinicalTrials.gov.
Veliparib (ABT-888) is an unapproved investigational drug under clinical development. Safety and efficacy have not been established.
- Donawho CK, Luo Y, Luo Y, et al. ABT-888, an orally active poly(ADP-ribose) polymerase inhibitor that potentiates DNA-damaging agents in preclinical tumor models. Clin Cancer Res. 2007;13(9):2728-2737.
- Palma JP, Wang YC, Rodriguez LE, et al. ABT-888 confers broad in vivo activity in combination with temozolomide in diverse tumors. Clin Cancer Res. 2009;15(23):7277-7290.
- Plummer ER, Calvert H. Targeting poly(ADP-ribose) polymerase: a two-armed strategy for cancer therapy. Clin Cancer Res. 2007;13(21):6252-6256.
- Owonikoko TK, Zhang G, Deng X, et al. Poly (ADP) ribose polymerase enzyme inhibitor, veliparib, potentiates chemotherapy and radiation in vitro and in vivo in small cell lung cancer. Cancer Med. 2014;3(6):1579-1594.
- Cheng H, Zhang Z, Borczuk A, et al. PARP inhibition selectively increases sensitivity to cisplatin in ERCC1-low non-small cell lung cancer cells. Carcinogenesis. 2013;34(4):739-749.
- Kummar S, Wade JL, Oza AM, et al. Randomized phase II trial of cyclophosphamide and the oral poly (ADP-ribose) polymerase inhibitor veliparib in patients with recurrent, advanced triple-negative breast cancer. Invest New Drugs. 2016 Mar 21. [Epub ahead of print].
- Reiss KA, Herman JM, Zahurak M, et al. A phase I study of veliparib (ABT-888) in combination with low-dose fractionated whole abdominal radiation therapy in patients with advanced solid malignancies and peritoneal carcinomatosis. Clin Cancer Res. 2015;21(1):68-76.
Related Links
HER2-, BRCA+ Breast Cancer
Ovarian Cancer (Maintenance)
OVERVIEW
Budigalimab is a humanized, recombinant, IgG1 monoclonal antibody targeting PD-1, incorporating an Fc mutation to limit FcγR-mediated effector function.
PROPOSED MECHANISM OF ACTION
Programmed cell death-1 (PD1)/programmed cell death ligand-1 (PD-L1) interactions are part of an immune system checkpoint pathway that prevents T cells from causing damage to healthy cells. Tumor cells often overexpress PD-L1 to take advantage of this checkpoint and prevent an antitumor immune response.1,2
Budigalimab blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2, by binding to PD1. This prevents the inhibitory signaling pathway from being triggered when T cells encounter the tumor and restores the immune system's ability to recognize tumor cells as abnormal, allowing T cells to target these tumor cells for death.3
DEVELOPMENT
Budigalimab is being studied in phase 1 trials for the treatment of advanced solid tumors in combination with other agents.
CLINICAL TRIALS
View select clinical trials with budigalimab now. To view a full list of clinical trials in which budigalimab is being investigated, please visit ClinicalTrials.gov.
Budigalimab is an unapproved investigational drug under clinical development. Safety and efficacy have not been established.
- Ohaegbulam KC, Assal A, Lazar-Molnar E, Yao Y, Zang X. Human cancer immunotherapy with antibodies to the PD-1 and PD-L1 pathway. Trends Mol Med. 2015;21(1):24-33.
- Freeman GJ, Long AJ, Iwai Y, et al. Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. J Exp Med. 2000;192(7):1027-1034.
- Powderly et al. Model Informed Dosing Regimen and Phase I Results of the Anti-PD-1 Antibody Budigalimab (ABBV-181). Clin Transl Sci. 2021;14:277–287.
Related Links
Advanced Solid Tumors
OVERVIEW
ABBV-927 is a differentiated, agonistic anti-CD40 immuno-oncology monoclonal antibody (mAb) selected for enhanced activation of myeloid-lineage cells (moDC) versus B cells in early phase clinical development.
PROPOSED MECHANISM OF ACTION
CD40 is the key costimulatory cell surface receptor that functions as a master switch for both the innate and adaptive immune systems. As a member of the tumor necrosis factor receptor superfamily (TNFRSF), CD40 is widely expressed, including on antigen-presenting cells (APCs) such as dendritic cells, monocytes, macrophages, and B cells.1
ABBV-927 is an agnostic CD40 mAb that was selected for its potency on myeloid-lineage cells and binds to CD40 on a variety of immune cell types. An agonistic anti-CD40 antibody can achieve potent anti-tumor immunity through initiating antigen presentation, promoting adaptive immunity, and reprogramming a suppressive tumor microenvironment while the effect of CD40 agonism depends on the type of cell expressing CD40.1,2
DEVELOPMENT
ABBV-927 is being studied in phase 1 trials for the treatment of pancreatic cancer, triple negative breast cancer, and advanced solid tumors as monotherapy or in combination with other agents. More specifically, expansion cohorts have or will evaluate ABBV-927 in patients with non-small cell lung cancer, squamous cell carcinoma of the head and neck, and triple negative breast cancer.
CLINICAL TRIALS
View select clinical trials with ABBV-927 now. To view a full list of clinical trials in which ABBV-927 is being investigated, please visit ClinicalTrials.gov.
ABBV-927 is an unapproved investigational drug under clinical development. Safety and efficacy have not been established.
- Vonderheide RH, Glennie MJ. Agonistic CD40 antibodies and cancer therapy. Clin Cancer Res. 2013;19(5):1035-1043.
- National Cancer Institute. NCI Drug Dictionary. ABBV-927. https://www.cancer.gov/publications/dictionaries/cancer-drug/def/anti-cd40-agonist-monoclonal-antibody-abbv-927. Accessed July 2019.
Related Links
Advanced Solid Tumors
Triple Negative Breast Cancer
Pancreatic Cancer
OVERVIEW
ABBV-151 is a humanized monoclonal antibody inhibitor of GARP-TGF-β1 that is being investigated in early-phase clinical development.
PROPOSED MECHANISM OF ACTION
Regulatory T-cells (Tregs) expressing the GARP-TGF-β1 complex dampen immune responses and can inhibit the immune response to tumor cells1,2 GARP complexes with latent TGF-β1 on human Tregs; upon T-cell receptor (TCR) stimulation, Tregs release active TGF-β1 from the GARP-TGF-β1 complex, suppressing anti-tumor cell immune responses.3
ABBV-151 binds the GARP-TGF-β1 complex, and blocks the release of active TGF-β1, thereby limiting the immunosuppressive activity of activated Tregs, enabling effector T cells (Teffector) cells to attack cancer cells.1,2
(Adapted from Metelli A, et al. Journal of Hematology & Oncology (2018) 11:24. http://creativecommons.org/licenses/by/4.0/ for CC BY 4.0)
DEVELOPMENT
ABBV-151 is being investigated in a phase 1 study for the treatment of patients with advanced solid tumors.
Used alone or in combination with an antibody targeting PD1, ABBV-151 may improve the efficiency of immunotherapy.4
CLINICAL TRIALS
View select clinical trials with ABBV-151 now. To view a full list of clinical trials in which ABBV-151 is being investigated, please visit ClinicalTrials.gov.
ABBV-151 is an unapproved investigational drug under clinical development. Safety and efficacy have not been established.
- Metelli A, et al. Immunoregulatory functions and the therapeutic implications of GARP-TGF-β in inflammation and cancer. J Hematol Oncol 2018; 11:24.
- Metelli A, et al . Surface Expression of TGFβ Docking Receptor GARP Promotes Oncogenesis and Immune Tolerance in Breast Cancer. Cancer Res 2016; 76:7106–7117.
- Stockis et al. Comparison of stable human Treg and Th clones by transcriptional profiling. Eur J Immunol. 2009 Mar;39(3):869-82.
- Cuende J, et al. Monoclonal antibodies against GARP/TGF-β1 complexes inhibit the immunosuppressive activity of human regulatory T cells in vivo. Sci Transl Med. 2015;7(284):284ra56.
Related Links
Advanced Solid Tumors
OVERVIEW
Mirzotamab clezutoclax (ABBV-155) is a B7H3-targeted antibody drug conjugate (ADC), in early-phase clinical development.
PROPOSED MECHANISM OF ACTION
B7H3 is an immunomodulatory transmembrane N-linked glycoprotein that is overexpressed in a number of solid tumors including small cell lung cancer, non-small cell lung cancer, breast cancer, and others.
The binding of mirzotamab clezutoclax to B7H3 on the cell surface leads to ADC internalization, linker cleavage, and intracellular releasing of the payload, which results in apoptotic cell death.
DEVELOPMENT
Mirzotamab clezutoclax (ABBV-155) is being investigated in a phase 1 study for the treatment of patients with advanced solid tumors.
CLINICAL TRIALS
View select clinical trials with mirzotamab clezutoclax now. To view a full list of clinical trials in which mirzotamab clezutoclax is being investigated, please visit ClinicalTrials.gov.
Mirzotamab clezutolcax is an unapproved investigational drug under clinical development. Safety and efficacy have not been established.
Related Links
Advanced Solid Tumors
OVERVIEW
TTX-030 is an anti-CD39 monoclonal antibody that is being investigated in lymphoma and solid tumors.
PROPOSED MECHANISM OF ACTION1,2
In solid tumors, ATP is abundantly released in the extracellular space, leading to an accumulation of extracellular ATP (eATP) levels far in excess of those found in healthy tissues. Extracellular ATP acts as a proinflammatory stimulus by agonizing P2 purinergic receptors in immune cells.
Tumors are proficient at scavenging eATP, converting it to immunosuppressive adenosine by means of two ectonucleotidases, CD39 and CD73. CD39 hydrolyzes ATP converting it to adenosine monophosphate (AMP), which can in turn be converted to adenosine by CD73. Adenosine acts on P1 receptors found ubiquitously on immune cells, causing immunosuppression, and therefore has anti-inflammatory effects.
TTX-030 inhibits CD39 enzymatic activity, thus preventing hydrolysis of proinflammatory ATP to immunosupressive adenosine resulting in a preservation of immune cell function and tumor clearance.
DEVELOPMENT
TTX-030 is being investigated as a monotherapy and in combination with a PD1 inhibitor or chemotherapy in patients with solid tumors.
CLINICAL TRIALS
View select clinical trials with TTX-030 now. To view a full list of clinical trials in which TTX-030 is being investigated, please visit ClinicalTrials.gov.
TTX-030 is an unapproved investigational drug under clinical development. Safety and efficacy have not been established.
- Pellegatti P, Raffaghello L, Bianchi G, Piccardi F, Pistoia V, Di Virgilio F. Increased level of extracellular ATP at tumor sites: in vivo imaging with plasma membrane luciferase. PLoS One 2008;3:e2599.
- Takenaka MC, Robson S, Quintana FJ. Regulation of the T cell response by CD39. Trends Immunol 2016;37:427-39.
Related Links
Solid Tumors
OVERVIEW
ABBV-CLS-484 is a PTPN2/N1 small molecule inhibitor (SMI).
PROPOSED MECHANISM OF ACTION1-4
ABBV-CLS-484 is a small molecule that binds to ubiquitously expressed protein tyrosine phosphatase non-receptor type 2 (PTPN2) and type 1 (PTPN1). Importantly, PTPN2/N1 inhibition drives both tumor cell dependent and immune cell dependent anti-cancer mechanisms of action. PTPN2/N1 inhibition in tumor cells blocks IFN signaling through the JAK/STAT pathway resulting in growth delay, increased tumor antigen presentation, and elevated pro-inflammatory chemokine release. Additionally, PTPN2/N1 inhibition promotes the activation and proinflammatory anti-tumorigenic function of multiple immune cell subsets. In T cells, PTPN2 acts as a negative regulator of TCR signaling whereby inhibition of these enzymes results in T cell activation, proliferation and immune effector functions, including tumoricidal action.
DEVELOPMENT
ABBV-CLS-484 is being investigated in a phase 1 study as a monotherapy and in combination with a PD-1 inhibitor for the treatment of patients with metastatic or locally advanced solid tumor cancer.
CLINICAL TRIALS
View select clinical trials with ABBV-CLS-484 now. To view a full list of clinical trials in which ABBV-CLS-484 is being investigated, please visit ClinicalTrials.gov.
ABBV-CLS-484 is an unapproved investigational drug under clinical development. Safety and efficacy have not been established.
- Heinonen KM, et al. T-cell protein tyrosine phosphatase deletion results in progressive systemic inflammatory disease. Blood. 2004;103(9):3457-3464.
- Wiede, F. et al. T cell protein tyrosine phosphatase attenuates T cell signaling to maintain tolerance in mice. J Clin Invest. 2011;121:4758-4774.
- Hering L, et al. Protein Tyrosine Phosphatase Non-Receptor Type 2 Function in Dendritic Cells Is Crucial to Maintain Tissue Tolerance. Frontiers in Immunology. 2020;11:1856.
- Manguso RT, et al. In vivo CRISPR screening identifies Ptpn2 as a cancer immunotherapy target. Nature. 2017;547(7664):413-418.
Related Links
Advanced Solid Tumor Cancer
OVERVIEW
ABBV-CLS-579 is a PTPN2/N1 small molecule inhibitor (SMI).
PROPOSED MECHANISM OF ACTION1-3
ABBV-CLS-579 is a small molecule that binds to ubiquitously expressed protein tyrosine phosphatase non-receptor type 2 (PTPN2) and type 1 (PTPN1). Importantly, PTPN2/N1 inhibition drives both tumor cell dependent and immune cell dependent anti-cancer mechanisms of action. PTPN2/N1 inhibition in tumor cells promotes IFN signaling through the JAK/STAT pathway resulting in growth delay, increased tumor antigen presentation, and elevated pro-inflammatory chemokine release. Additionally, PTPN2/N1 inhibition promotes the activation and proinflammatory anti-tumorigenic function of multiple immune cell subsets. In T cells, PTPN2 acts as a negative regulator of TCR signaling whereby inhibition of these enzymes results in T cell activation, proliferation and immune effector functions, including tumoricidal action.
DEVELOPMENT
ABBV-CLS-579 is being investigated in a phase 1 study as a monotherapy and in combination with a PD-1 inhibitor for the treatment of patients with metastatic or locally advanced solid tumor cancer.
CLINICAL TRIALS
View select clinical trials with ABBV-CLS-579 now. To view a full list of clinical trials in which ABBV-CLS-579 is being investigated, please visit ClinicalTrials.gov.
ABBV-CLS-579 is an unapproved investigational drug under clinical development. Safety and efficacy have not been established.
- Heinonen KM, et al. T-cell protein tyrosine phosphatase deletion results in progressive systemic inflammatory disease. Blood. 2004;103(9):3457-3464.
- Wiede, F. et al. T cell protein tyrosine phosphatase attenuates T cell signaling to maintain tolerance in mice. J Clin Invest. 2011;121:4758-4774.
- Hering L, et al. Protein Tyrosine Phosphatase Non-Receptor Type 2 Function in Dendritic Cells Is Crucial to Maintain Tissue Tolerance. Frontiers in Immunology. 2020;11:1856.
- Manguso RT, et al. In vivo CRISPR screening identifies Ptpn2 as a cancer immunotherapy target. Nature. 2017;547(7664):413-418.
Related Links
Advanced Solid Tumor Cancer
OVERVIEW
ABBV-637 is designed to be a first-in-class ADC to target the epidermal growth factor receptor (EGFR) and to deliver a BCL-XL inhibitor.
PROPOSED MECHANISM OF ACTION
EGFR is a potent oncogene overexpressed and/or mutated in various solid tumors including NSCLC.
BCL-XL acts as a pro-survival protein by preventing the release of cytochrome C, or other mitochondrial contents, thereby inhibiting programmed cell death. BCL-XL is overexpressed in NSCLC and other solid tumors and is associated with chemo-refractory disease and poor prognosis.
ABBV-637 targets a cryptic epitope of EGFR that is selectively exposed on EGFR-overexpressing tumor cells relative to normal, healthy tissues. ABBV-637 binds to EGFR on the surface of tumor cells, which leads to internalization of the ADC, thereby inhibiting BCL-XL and resulting in apoptotic cell death.
DEVELOPMENT
ABBV-637 is being studied in a phase 1 trial for the treatment of solid tumors, specifically non-small cell lung cancer (NSCLC) in combination with docetaxel or osimertinib.
CLINICAL TRIALS
View select clinical trials with ABBV-637 now. To view a full list of clinical trials in which ABBV-637 is being investigated, please visit ClinicalTrials.gov.
ABBV-637 is an investigational drug for clinical study only. Safety and efficacy have not been established
- Rotow J, et al. First-in-human phase 1 study of ABBV-637 as monotherapy and in combination in patients with relapsed and refractory solid tumors. Poster 1185 TiP. ESMO 2022. Paris, France.
Related Links
Solid tumors
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