Pipeline

Explore Our Pipeline

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.

Hematologic Malignancies

Phase 1

Phase 2

Phase 3

Overview

Venetoclax (ABT-199/GDC-0199) is a selective, orally bioavailable small-molecule BCL-2 inhibitor.1

Proposed Mechanism of Disease

The balance between pro-death and pro-survival molecules determines whether a cell lives or dies.2,3 BCL-2 is a pro-survival protein that binds and sequesters pro-death (pro-apoptotic) proteins, such as BIM, limiting their ability to initiate apoptosis (cell death).

Venetoclax is designed to bind to BCL-2, preventing it from binding to pro-apoptotic proteins and thereby restoring the cell's ability to undergo apoptosis.1

Development

Venetoclax FDA approval timeline:4

  • April 2016 (accelerated approval): Monotherapy for the treatment of Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL) with 17p deletion
  • June 2018: Venetoclax in combination with rituximab for the treatment of CLL or small lymphocytic lymphoma (SLL), with or without 17p deletion, who have received at least one prior therapy.
  • November 2018 (accelerated approval): Venetoclax in combination with azacitidine or decitabine or low-dose cytarabine (LDAC) for the treatment of newly-diagnosed acute myeloid leukemia (AML) in adults ≥75 years, or who have comorbidities that preclude use of intensive induction chemotherapy
  • May 2019: Expanded indication to include the treatment of adult patients with CLL or SLL, based on the data from the CLL14 study of venetoclax plus obinutuzumab in first-line CLL patients
  • October 2020: Venetoclax in combination with azacitidine, or decitabine, or low-dose cytarabine (LDAC) for the treatment of newly diagnosed acute myeloid leukemia (AML) in adults 75 years or older, or who have comorbidities that preclude use of intensive induction chemotherapy

AbbVie and Genentech continue to investigate venetoclax in ongoing Phase 3 and early phase clinical trials for the treatment of CLL and SLL, as well as a variety of other cancers, including AML, multiple myeloma (MM), myelodysplastic syndromes (MDS), subtypes of non-Hodgkin lymphoma (NHL) [mantle cell lymphoma (MCL), Waldenstrom's macroglobulinemia (WM), diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL)] and acute lymphoblastic leukemia (ALL).

VENETOCLAX INDICATION AND SAFETY OVERVIEW FOR AML/CLL (US PRESCRIBING INFORMATION).4

Indication:

Venetoclax is a BCL-2 inhibitor indicated:

  • For the treatment of adult patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL).
  • In combination with azacitidine, or decitabine, or low-dose cytarabine for the treatment of newly diagnosed acute myeloid leukemia (AML) in adults:
    • who are age 75 years or older, or
    • who have comorbidities that preclude use of intensive induction chemotherapy.

SAFETY INFORMATION

Contraindications

  • Strong CYP3A Inhibitors: Concomitant use with strong CYP3A inhibitors at initiation and during ramp-up phase in patients with CLL/SLL is contraindicated.

Warnings and Precautions

  • TLS: Tumor lysis syndrome (TLS), including fatal events and renal failure requiring dialysis, has occurred in patients treated with venetoclax. Anticipate TLS; assess risk in all patients. Premedicate with anti-hyperuricemics and ensure adequate hydration. Employ more intensive measures (intravenous hydration, frequent monitoring, hospitalization) as overall risk increases.
  • Neutropenia: Monitor blood counts. Interrupt dosing and resume at same or reduced dose. Consider supportive care measures.
  • Infections: Fatal and serious infections such as pneumonia and sepsis have occurred in patients treated with venetoclax. Monitor for signs and symptoms of infection and treat promptly. Withhold venetoclax for Grade 3 and 4 infection until resolution and resume at same or reduced dose.
  • Immunization: Do not administer live attenuated vaccines prior to, during, or after venetoclax treatment until B-cell recovery.
  • Embryo-Fetal Toxicity: May cause embryo-fetal harm. Advise females of reproductive potential of the potential risk to a fetus and to use effective contraception.
  • Increased mortality in patients with multiple myeloma (MM) when venetoclax is added to bortezomib and dexamethasone. In a randomized trial in patients with relapsed or refractory MM, the addition of venetoclax to bortezomib plus dexamethasone, a use for which venetoclax is not indicated, resulted in increased mortality. Treatment of patients with MM with venetoclax in combination with bortezomib plus dexamethasone is not recommended outside of controlled clinical trials.

Adverse Reactions

  • In CLL/SLL, the most common adverse reactions (≥20%) for venetoclax when given in combination with obinutuzumab or rituximab or as monotherapy were neutropenia, thrombocytopenia, anemia, diarrhea, nausea, upper respiratory tract infection, cough, musculoskeletal pain, fatigue, and edema.
  • In AML, the most common adverse reactions (≥30%) in combination with azacitidine, or decitabine, or low-dose cytarabine were nausea, diarrhea, thrombocytopenia, constipation, neutropenia, febrile neutropenia, fatigue, vomiting, edema, pyrexia, pneumonia, dyspnea, hemorrhage, anemia, rash, abdominal pain, sepsis, musculoskeletal pain, dizziness, cough, oropharyngeal pain, and hypotension.

Review full prescribing information for additional information at www.rxabbvie.com.

Clinical Trials

View select clinical trials with venetoclax now. To view a full list of clinical trials in which venetoclax is being investigated, please visit ClinicalTrials.gov.

Venetoclax (ABT-199/GDC-0199) is an approved drug being studied for unapproved uses. Safety and efficacy have not been established for these unapproved uses.

  1. Souers AJ, Leverson JD, Boghaert ER, et al. ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets. Nat Med. 2013;19(2):202-208.
  2. Billard C. Apoptosis inducers in chronic lymphocytic leukemia. Oncotarget. 2014;5(2):309-25.
  3. Davids MS, Letai A. Targeting the B-cell lymphoma/leukemia 2 family in cancer. J Clin Oncol. 2012;30(25):3127–3135.
  4. Drugs@FDA: FDA Approved Drug Products – VENCLEXTA. Accessed at https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=208573.
  5. Venetoclax [package insert]. North Chicago, IL: AbbVie, Inc. and South San Francisco, CA: Genentech, Inc.: Nov 2020.

Acute Myeloid Leukemia(AML)

Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL)

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 Disease

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, 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.

  1. Tse C, et al. ABT-263: a potent and orally bioavailable Bcl-2 family inhibitor. Cancer Res. 2008;68(9):3421-3428.
  2. 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.
  3. Alexander T, et al. ASCO Annual Meeting 2018. TPS10575 Journal of Clinical Oncology 36, no. 15_suppl.
  4. Khaw et al. Venetoclax responses of pediatric ALL xenografts reveal sensitivity of MLL-rearranged leukemia. Blood. 2016;128:1382-95.
  5. 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.
  6. 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.

Myelofibrosis (MF)

Myeloproliferative Neoplasms (MPNs)

Overview

Epcoritamab (ABBV-GEN3013) is an immunotherapy and an IgG1 bispecific antibody targeting CD3 and CD20 in early phase clinical development.1,2

MECHANISM OF DISEASE

Epcoritamab is a subcutaneously administered, bispecific CD3×CD20 antibody created via Fab-arm exchange using the unique DuoBody® technology platform that allows retaining of the regular IgG1 antibody structure and a long plasma half-life.3

CD20 is a clinically well-validated target that is expressed in a wide variety of B-cell malignancies. Epcoritamab binds to CD20 B-cells, and simultaneously to CD3 on T-cells, inducing activation and cytotoxic activity of T cells.1

Upon the bispecific binding of CD3 on T cells and CD20 malignant B cells, an immunological synapse is formed between the bound T and B cell, resulting in perforin/granzyme B-induced apoptosis of the malignant B cells.1

T-cell activation—a result of the CD20-CD3 interaction—promotes the proliferation/expansion of T-cells, which may lead to malignant B-cell killing.3

®A registered trademark of Genmab A/S

DEVELOPMENT

Epcoritamab is being investigated for the treatment of B-NHL across different histologies and settings (R/R and 1L).

Clinical Trials

View select clinical trials with epcoritamab now. To view a full list of clinical trials in which epcoritamab is being investigated, please visit ClinicalTrials.gov.

Epcoritamab is an unapproved investigational drug under clinical development. Safety and efficacy have not been established.

  1. Hutchings M, et al. Epcoritamab (GEN3013; DuoBody-CD3×CD20) to induce complete response in patients with relapsed/refractory B-cell non-Hodgkin lymphoma: Complete dose escalation data and efficacy results from a phase I/II trial. Poster #8009. 56th Annual ASCO Meeting and Exposition; May 29 – June 2, 2020; Virtual Format.
  2. Engelberts PJ, et al. DuoBody-CD3xCD20 induces potent T-cell-mediated killing of malignant B cells in preclinical models and provides opportunities for subcutaneous dosing. EBioMedicine. 2020;52:102625.
  3. 20191209_Genmab RD Update ASH Data Review
  4. ClinicalTrials.gov. NCT03625037. https://clinicaltrials.gov/ct2/show/NCT03625037. Accessed October 2020.
  5. EudraCT Number 2020-000845-15. https://www.clinicaltrialsregister.eu/ctr-search/trial/2020-000845-15/DK/. Accessed November 2020.
  6. ClinicalTrials.gov. NCT04542824. https://clinicaltrials.gov/ct2/show/NCT04542824. Accessed October 2020.
  7. ClinicalTrials.gov. NCT04623541. https://clinicaltrials.gov/ct2/show/NCT04623541. Accessed November 2020.
  8. ClinicalTrials.gov. NCT04628494. https://clinicaltrials.gov/ct2/show/NCT04628494. Accessed November 2020.

Diffuse Large B-Cell Lymphoma (DLBCL)

Non-Hodgkin Lymphoma (NHL)

Chronic Lymphocytic Leukemia (CLL)

Overview

Lemzoparlimab/TJC4 is an anti-CD47 monoclonal antibody that is in early phase clinical development.

PROPOSED MECHANISM OF DISEASE

CD47 is a cell surface transmembrane protein that is expressed by nearly all cells of the human body and plays a key role and plays a key role in the immune system recognition of "self" and macrophage phagocytic activity. By overexpressing CD47 to bind to SIRPα on macrophages, cancer cells exploit the CD47-SIRPα pathway to send a strong, anti-phagocytic "Don't Eat Me" signal to the immune system. Inhibition of CD47-SIRPα binding through CD47 blockade can neutralize the "Don't Eat Me" signal and expose a cancer cell's "Eat Me" signal.1

Lemzoparlimab/TJC4 is a clinically advanced CD47 inhibitor with a differentiated approach to blocking CD47-SIRPα signaling. Due to a unique binding epitope, lemzoparlimab/TJC4 exhibits limited binding to glycosylated CD47 on RBCs, sparing them from macrophage attack.2,3

  • Crystal structure identified a glycosylation site located near lemzoparlimab/TJC4's specific binding epitope residues with RBCs.
  • Glycosylation of RBCs may influence the epitope exposure and advantageously diminish the binding of lemzoparlimab/TJC4 to RBC.

DEVELOPMENT

Lemzoparlimab/TJC4 is being studied in phase 1/2 trials for the treatment of hematologic malignancies (AML/MDS) and advanced solid tumors as monotherapy or in combination with other agents. Expansion cohorts will evaluate lemzoparlimab/TJC4 in patients with non-small cell lung cancer, Urothelial (bladder) cancer, Epithelial ovarian cancer, fallopian tube, or primary peritoneal cancer, and DLBCL or Indolent B-cell Lymphoma.

Clinical Trials

View select clinical trials with lemzoparlimab/TJC4 now. To view a full list of clinical trials in which lemzoparlimab/TJC4 is being investigated, please visit ClinicalTrials.gov.

Lemzoparlimab/TJC4 is an unapproved investigational drug under clinical development. Safety and efficacy have not been established.

  1. Chao MP, et al. "Therapeutic Targeting of the Macrophage Immune Checkpoint CD47 in Myeloid Malignancies". Front Oncol. 2020 Jan 22;9:1380.
  2. I-Mab Biopharma, 2020 SITC presentation, November 13, 2020 (https://www.i-mabbiopharma.com/lemzoparlimab_data_readout.pdf).
  3. Berlin J, et al. "A first-in-human study of lemzoparlimab, a differentiated anti-CD47 antibody, in subjects with relapsed/refractory malignancy: initial monotherapy results". Society for Immunotherapy of Cancer (SITC) 2020 Annual Meeting. Abstract 385

Advanced Solid Tumors and Lymphomas

Acute Myeloid Leukemia (AML)

Myelodysplastic Syndromes (MDS)

Overview

ABBV-GEN3009 is a DuoHexaBody® bispecific CD37 antibody which enables dual targeting for two non-overlapping epitopes on CD37.1

PROPOSED MECHANISM OF DISEASE

ABBV-GEN3009 targets two different, non-overlapping epitopes on CD37, a target broadly expressed on malignant B cells in a variety of B-cell lymphomas and leukemias, including B-NHL and CLL.1

CD37 is selectively expressed on mature B cells and has limited or no expression on other hematopoietic cells such as T cells and NK cells, granulocytes, monocytes, and dendritic cells.1

To enhance complement-dependent cytotoxicity (CDC), the E430G mutation was introduced to drive more efficient IgG hexamer formation through intermolecular Fc-Fc interactions after cell surface antigen binding.1

Preclinically, high CDC potency observed with ABBV-GEN3009 was attributed to enhanced IgG hexamerization mediated by the E430G mutation in combination with dual epitope targeting.1

ABBV-GEN3009 also induces potent FcγR-mediated effector functions in preclinical studies, including Antibody-Dependent Cell Cytotoxicity (ADCC) and Antibody-Dependent Cellular Phagocytosis (ADCP).1

®A registered trademark of Genmab A/S

DEVELOPMENT

ABBV-GEN3009 is being studied in a first-in-human Phase 1/2a trial as a monotherapy for safety and efficacy in patients with R/R B-cell NHL.

Clinical Trials

View select clinical trials with ABBV-GEN3009 now. To view a full list of clinical trials in which ABBV-GEN3009 is being investigated, please visit ClinicalTrials.gov.

ABBV-GEN3009 is an unapproved investigational drug under clinical development. Safety and efficacy have not been established.

  1. Oostindie SC, et al. DuoHexaBody-CD37®, a biparatopic CD37 antibody with enhanced Fc-mediated hexamerization as a potential therapy for B-cell malignancies. Blood Cancer Journal. 2020;10:30.
  2. ClinicalTrials.gov. NCT04358458. https://clinicaltrials.gov/ct2/show/NCT04358458. Accessed November 2020

Non-Hodgkin Lymphoma (NHL)

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 DISEASE1,2

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 trials. First as a monotherapy (in patients with previously-treated solid tumors); in combination with chemotherapy (in patients with previously-treated colorectal cancer); and in combination with venetoclax (in patients with previously-treated hematologic malignancies). Eftozanermin alfa is also being investigated 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.

  1. 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.
  2. 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.

Multiple Myeloma (MM)

Advanced Solid & Hematologic Malignancies

Overview

Mivebresib (ABBV-075) is an orally active small-molecule bromodomain (BRD) and extra-terminal motif (BET) inhibitor.1

PROPOSED MECHANISM OF DISEASE

BRD and BET Proteins are a Bromodomain Subfamily
Which Includes BRD2, BRD3, BRD4, and BRDT

The BET family (BRD2, BRD3, BRD4, and BRDT) are bromdomain-containing proteins that interact with acetylated histone tails and transcription factors which play important roles in transcription regulation.2 The BET family of proteins is characterized by the presence of 2 tandem bromodomains (BDI and BDII) and an extra-terminal domain.3 BET bromodomains recognize acetylated lysines on transcription factors and histones, facilitating transcription of key genes involved in tumorigenesis (eg, c-myc, androgen receptor).3,4

In murine models of myeloproliferative neoplasm, bromodomain and extra-terminal family protein inhibitors (BETi) reduced inflammatory cytokine levels and, combined with JAKi, reduced MF disease burden.5 BETi also modulated key nodes in the intrinsic apoptosis pathway and synergized with the B-cell lymphoma-2 (BCL-2) family inhibitor navitoclax (Nav) in solid tumor models.6

Clinical Trials

View select clinical trials with mivebresib now. To view a full list of clinical trials in which mivebresib is being investigated, please visit ClinicalTrials.gov.

Mivebresib (ABBV-075) is an unapproved investigational drug under clinical development. Safety and efficacy have not been established.

  1. McDaniel KF, et al. Discovery of N-(4-(2,4-Difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)ethanesulfonamide (ABBV-075/Mivebresib), a Potent and Orally Available Bromodomain and Extraterminal Domain (BET) Family Bromodomain Inhibitor. J Med Chem. 2017;60(20):8369-8384.
  2. Pfister SX, et al. Marked for death: targeting epigenetic changes in cancer. Nat Rev Drug Discov. 2017 Apr;16(4):241-263.
  3. Xu Y, Vakoc CR. Targeting Cancer Cells with BET Bromodomain Inhibitors. Cold Spring Harb Perspect Med. 2017;7(7):a026674
  4. Delmore JE, et al. BET bromodomain inhibition as a therapeutic strategy to target c-Myc. Cell. 2011;146(6):904-917.
  5. Kleppe M, et al. Dual Targeting of Oncogenic Activation and Inflammatory Signaling Increases Therapeutic Efficacy in Myeloproliferative Neoplasms. Cancer Cell 2018;33:29-43.
  6. Mascarenhas J, et al. Two Phase 1b Studies Evaluating the Safety and Tolerability of BET Inhibitors, ABBV-744 and Mivebresib, as Monotherapies and in Combination with Ruxolitinib or Navitoclax in Patients with Myelofibrosis. Poster #634. ASH Annual Meeting; December 5-8, 2020; Virtual Format.

Myelofibrosis (MF)

Overview

ABBV-744 is a bromodomain II (BDII)-selective extra-terminal motif (BET) bromodomain protein inhibitor in early phase clinical development.

Proposed Mechanism of Disease

The BET family (BRD2, BRD3, BRD4, and BRDT) are bromdomain-containing proteins that interact with acetylated histone tails and transcription factors which play important roles in transcription regulation.1

The BET family of proteins is characterized by the presence of 2 tandem bromodomains (BDI and BDII) and an extra-terminal domain.2 BET bromodomains recognize acetylated lysines on transcription factors and histones, facilitating transcription of key genes involved in tumorigenesis (eg, c-myc, androgen receptor).2,3

ABBV-744 binds with high selectivity to the BDII of BET proteins, thereby releasing the BET proteins and their cofactors from chromatin.1 Inhibition of BET proteins thus has the potential to suppress transcription of key genes involved in tumorigenesis.

Development

ABBV-744 monotherapy is being studied in a phase 1 clinical trial in patients with myelofibrosis (MF).

Clinical Trials

View select clinical trials with ABBV-744 now. To view a full list of clinical trials in which ABBV-744 is being investigated, please visit ClinicalTrials.gov.

ABBV-744 is an unapproved investigational drug under clinical development. Safety and efficacy have not been established.

  1. Pfister SX, et al. Marked for death: targeting epigenetic changes in cancer. Nat Rev Drug Discov. 2017 Apr;16(4):241-263.
  2. Xu Y, Vakoc CR. Targeting Cancer Cells with BET Bromodomain Inhibitors. Cold Spring Harb Perspect Med. 2017;7(7):a026674
  3. Delmore JE, et al. BET bromodomain inhibition as a therapeutic strategy to target c-Myc. Cell. 2011;146(6):904-917.

Myelofibrosis (MF)

Overview

ABBV-467 is a small molecule inhibitor (SMI) of MCL-1.

PROPOSED MECHANISM OF DISEASE

MCL-1, an anti-apoptotic protein belonging to the B-cell lymphoma 2 (BCL-2) family of proteins, is upregulated in cancer cells and promotes tumor cell survival.1

ABBV-467 is an inhibitor of induced myeloid leukemia cell differentiation protein (myeloid cell leukemia-1; MCL-1; BCL-2-L-3), with potential pro-apoptotic and antineoplastic activities.1

Upon administration, MCL-1 inhibitor ABBV-467 targets and binds to MCL-1, thereby preventing the binding of MCL-1 to and inactivation of certain pro-apoptotic proteins.1

This promotes apoptosis of cells overexpressing MCL-1. 1


DEVELOPMENT

ABBV-467 is being studied in phase 1 trials for the treatment of R/R MM and other previously treated hematologic malignancies as monotherapy.

Clinical Trials

View select clinical trials with ABBV-467 now. To view a full list of clinical trials in which ABBV-467 is being investigated, please visit ClinicalTrials.gov.

ABBV-467 is an unapproved investigational drug under clinical development. Safety and efficacy have not been established.

  1. https://www.cancer.gov/publications/dictionaries/cancer-drug/def/802326.
  2. Lim B, et al. Novel Apoptosis-Inducing Agents for the Treatment of Cancer, a New Arsenal in the Toolbox. Cancers. 2019;11:1087; doi:10.3390/cancers11081087.
  3. Hird AW, et al. Recent advances in the development of Mcl-1 inhibitors for cancer therapy. Pharmacology & Therapeutics. 2019;198:59–67.
  4. ClinicalTrials.gov. NCT04178902. https://clinicaltrials.gov/ct2/show/NCT04178902. Accessed October 2020.

Multiple Myeloma (MM)

Overview

ABBV-184 is a bispecific molecule targeting CD3 on T cells and a survivin (BIRC5)-derived peptide bound to HLA-A2 expressed on tumor cells.

PROPOSED MECHANISM OF DISEASE

ABBV-184, comprised of a soluble high affinity T cell receptor (TCR) and an anti-CD3 binding domain, redirects effector T cells to tumor cells expressing a survivin peptide complexed to HLA-A2, the most common class I MHC allele 1,2. Survivin is an attractive intracellular tumor target expressed in multiple solid and hematological cancers that is readily amenable to TCR-directed - but not antibody-based - therapeutics. The selective high affinity (sub nM) that ABBV-184 exhibits for the survivin peptide may minimize on-target CD3 binding in T-cell rich tissues such as lymph nodes and spleen rather than tumor tissues, thereby mitigating the potential for cytokine release syndrome or other toxicities commonly associated with CD3 bispecific molecules.2,3

Cytotoxic T lymphocytes (CTLs) activated by tumor-associated antigen HLA-restricted epitopes play a key role in specifically killing cancer cells by directly lysing tumor cells and secreting cytokines such as IFN-γ, TNF-α, and IL-2.4

ABBV-184 was engineered to incorporate antibody Fc domains to optimize serum stability and improve pharmacokinetics for a durable half-life.2

ABBV-184: A Survivin Specific TCR/CD3 Bispecific Therapeutic


DEVELOPMENT

ABBV-184 is being studied in a phase 1 trial for the treatment of R/R AML and NSCLC as monotherapy.

Clinical Trials

View select clinical trials with ABBV-184 now. To view a full list of clinical trials in which ABBV-184 is being investigated, please visit ClinicalTrials.gov.

ABBV-184 is an unapproved investigational drug under clinical development. Safety and efficacy have not been established.

  1. Slaney CY, et al. CARs versus BiTEs: A Comparison between T Cell–Redirection Strategies for Cancer Treatment. Cancer Discov. 2018; 8:924.
  2. Reilly EB, et al. ABBV-184: A novel survivin specific T cell receptor/CD3 bispecific therapeutic that targets both solid tumor and hematological malignancies. Abstract #DDT03-01. AACR Virtual Annual Meeting 2020.
  3. Strohl WR and Naso M. Bispecific T-Cell Redirection versus Chimeric Antigen Receptor (CAR)-T Cells as Approaches to Kill Cancer Cells. Antibodies. 2019; 8:41.
  4. Wu Y, et al. HLA-A2-Restricted Epitopes Identified from MTA1 Could Elicit Antigen-Specific Cytotoxic T Lymphocyte Response. Journal of Immunology Research. 2018; Article ID 2942679.
  5. https://clinicaltrials.gov/ct2/show/NCT04272203. Accessed November 2020.

Acute Myeloid Leukemia (AML)

Lung cancer

Phase 1

Phase 2

Phase 3

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 Disease

The c-Met receptor tyrosine kinase is the cell surface receptor for hepatocyte growth factor (HGF) encoded by the MET protooncogene. c-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 c-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 being studied in a phase 2 clinical trial in patients with previously treated c-MET+ non-small cell lung cancer (NSCLC) and in a phase 1 trial in patients with advanced solid tumors.

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.

  1. 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.
  2. 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.

c-Met+ Non Small Cell Lung Cancer (NSCLC)

Breast and Ovarian Cancer

Phase 1

Phase 2

Phase 3

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 Disease

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.

  1. 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.
  2. 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.
  3. Plummer ER, Calvert H. Targeting poly(ADP-ribose) polymerase: a two-armed strategy for cancer therapy. Clin Cancer Res. 2007;13(21):6252-6256.
  4. 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.
  5. 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.
  6. 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].
  7. 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.

HER2-, BRCA+ Breast Cancer

Ovarian Cancer (Maintenance)

Solid Tumors

Phase 1

Phase 2

Phase 3

Overview

ABBV-GEN1044 is an Fc-silenced bispecific antibody targeting CD3 and 5T4.

PROPOSED MECHANISM OF DISEASE

The tumor-associated antigen 5T4 (also referred to as TPBG) is expressed across a wide range of solid cancer indications with limited expression in normal tissues.1

ABBV-GEN1044 is an Fc-silenced CD3 bispecific antibody that crosslinks CD3 on T cells with 5T4 on tumor cells.1

ABBV-GEN1044 Binds 5T4 on Tumor Cells and CD3 on T-cells

The mechanism of action ABBV-GEN1044 is to redirect T cells towards 5T4+ tumors cells, thereby inducing: T-cell activation and T-cell proliferation, inflammatory cytokine production, release of granzyme B and perforin, and T-cell mediated cytotoxicity in 5T4+ tumor cells.1

ABBV-GEN1044 showed preclinical anti-tumor activity in multiple solid cancer CDX/PDX models in humanized mice, which was associated with T-cell activation in the tumor and periphery in vivo.1

DEVELOPMENT

ABBV-GEN1044 is being studied in a first-in-human Phase 1/2a trial as a monotherapy for safety and efficacy in patients with malignant solid tumors.

Clinical Trials

View select clinical trials with ABBV-GEN1044 now. To view a full list of clinical trials in which ABBV-GEN1044 is being investigated, please visit ClinicalTrials.gov.

ABBV-GEN1044 is an unapproved investigational drug under clinical development. Safety and efficacy have not been established.

  1. Kemper K, et al. Preclinical mechanism of action and pharmacodynamic biomarker studies of DuoBody®-CD3x5T4 in vitro and in vivo in solid cancer models. Poster #704. SITC 2020. November 11-14, 2020.
  2. Dahlman A, et al. Preclinical safety and efficacy of a tumor-directed T cell activating 4-1BB x 5T4 ADAPTIR™ bispecific antibody. Poster #2380. AACR Annual Meeting. 2019; March 29-April 3, 2019; Atlanta, GA.
  3. Xu Y, et al. Preclinical development of T-cell receptor-engineered T-cell therapy targeting the 5T4 tumor antigen on renal cell carcinoma. Cancer Immunology, Immunotherapy. 2019;68:1979–1993.
  4. ClinicalTrials.gov. NCT04424641. https://clinicaltrials.gov/ct2/show/NCT04424641. Accessed November 2020.

Advanced Solid Tumors

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 DISEASE1,2

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 trials. First as a monotherapy (in patients with previously-treated solid tumors); in combination with chemotherapy (in patients with previously-treated colorectal cancer); and in combination with venetoclax (in patients with previously-treated hematologic malignancies). Eftozanermin alfa is also being investigated 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.

  1. 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.
  2. 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.

Advanced Solid & Hematologic Malignancies

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 Disease

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.

  1. 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.
  2. 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.
  3. 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.

Advanced Solid Tumors

Overview

ABBV-368 is a humanized immunoglobulin G1 anti-OX40 monoclonal antibody in early phase clinical development.

Proposed Mechanism of Disease

OX40 is a membrane-bound tumor necrosis factor (TNF)-receptor family member that is expressed on activated CD4+ and CD8+ T cells. OX40 is a costimulator of antigen-specific T-cell activation that is transiently upregulated after antigen stimulation. It is also constitutively expressed on activated regulatory T cells within the tumor.1

An OX40 agonist acts to prolong activation and subsequent differentiation of antitumor T cells and inhibits the function of T regulatory cells (Tregs) in the tumor microenvironment.1

ABBV-368 is an anti-OX40 monoclonal antibody (mAb) with ligand-like activity. Binding of ABBV-368 to OX40 may activate T-cell signaling and suppress Treg function.2

Development

ABBV-368 is being studied in phase 1 trials for the treatment of head and neck cancer, triple negative breast cancer and locally advanced or metastatic solid tumors as monotherapy or in combination with other agents.

Clinical Trials

View select clinical trials with ABBV-368 now. To view a full list of clinical trials in which ABBV-368 is being investigated, please visit ClinicalTrials.gov.

ABBV-368 is an unapproved investigational drug under clinical development. Safety and efficacy have not been established.

  1. Curti BD, et al. OX40 is a potent immune-stimulating target in late-stage cancer patients. Cancer Res. 2013;73(24):7189-7198.
  2. Spira A, et al. Safety, Tolerability, and Pharmacokinetics of the OX40 Agonist ABBV-368 in Patients With Advanced Solid Tumors. Poster #1149P. ESMO Annual Congress. Oct 19-23, 2018.

Head and Neck Squamous Cell Carcinoma (HNSCC)

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

CD40 and the Immune Response

DEVELOPMENT

ABBV-927 is being studied in phase 1 trials for the treatment of pancreatic cancer and advanced solid tumors as monotherapy or in combination with other agents. More specifically, expansion cohorts 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.

  1. Vonderheide RH, Glennie MJ. Agonistic CD40 antibodies and cancer therapy. Clin Cancer Res. 2013;19(5):1035-1043.
  2. 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.

Advanced Solid Tumors

Pancreatic Cancer

Overview

ABBV-011 is an antibody-drug conjugate (ADC) in early-phase clinical development.

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.

Small Cell Lung Cancer (SCLC)

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.

  1. Metelli A, et al. Immunoregulatory functions and the therapeutic implications of GARP-TGF-β in inflammation and cancer. J Hematol Oncol 2018; 11:24.
  2. 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.
  3. Stockis et al. Comparison of stable human Treg and Th clones by transcriptional profiling. Eur J Immunol. 2009 Mar;39(3):869-82.
  4. 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.

Advanced Solid Tumors

Overview

Mirzotamab clezutoclax (ABBV-155) is a B7H3-targeted antibody drug conjugate (ADC), in early-phase clinical development.

PROPOSED MECHANISM OF DISEASE

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.

Advanced Solid Tumors

Overview

Cofetuzumab pelidotin (ABBV-647) is a PTK7-targeted antibody-drug conjugate (ADC).

PROPOSED MECHANISM OF DISEASE1

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.

  1. 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.

Non-Small Cell Lung Cancer (NSCLC)

Overview

ABBV-184 is a bispecific molecule targeting CD3 on T cells and a survivin (BIRC5)-derived peptide bound to HLA-A2 expressed on tumor cells.

PROPOSED MECHANISM OF DISEASE

ABBV-184, comprised of a soluble high affinity T cell receptor (TCR) and an anti-CD3 binding domain, redirects effector T cells to tumor cells expressing a survivin peptide complexed to HLA-A2, the most common class I MHC allele 1,2. Survivin is an attractive intracellular tumor target expressed in multiple solid and hematological cancers that is readily amenable to TCR-directed - but not antibody-based - therapeutics. The selective high affinity (sub nM) that ABBV-184 exhibits for the survivin peptide may minimize on-target CD3 binding in T-cell rich tissues such as lymph nodes and spleen rather than tumor tissues, thereby mitigating the potential for cytokine release syndrome or other toxicities commonly associated with CD3 bispecific molecules.2,3

Cytotoxic T lymphocytes (CTLs) activated by tumor-associated antigen HLA-restricted epitopes play a key role in specifically killing cancer cells by directly lysing tumor cells and secreting cytokines such as IFN-γ, TNF-α, and IL-2.4

ABBV-184 was engineered to incorporate antibody Fc domains to optimize serum stability and improve pharmacokinetics for a durable half-life.2

ABBV-184: A Survivin Specific TCR/CD3 Bispecific Therapeutic


DEVELOPMENT

ABBV-184 is being studied in a phase 1 trial for the treatment of R/R AML and NSCLC as monotherapy.

Clinical Trials

View select clinical trials with ABBV-184 now. To view a full list of clinical trials in which ABBV-184 is being investigated, please visit ClinicalTrials.gov.

ABBV-184 is an unapproved investigational drug under clinical development. Safety and efficacy have not been established.

  1. Slaney CY, et al. CARs versus BiTEs: A Comparison between T Cell–Redirection Strategies for Cancer Treatment. Cancer Discov. 2018; 8:924.
  2. Reilly EB, et al. ABBV-184: A novel survivin specific T cell receptor/CD3 bispecific therapeutic that targets both solid tumor and hematological malignancies. Abstract #DDT03-01. AACR Virtual Annual Meeting 2020.
  3. Strohl WR and Naso M. Bispecific T-Cell Redirection versus Chimeric Antigen Receptor (CAR)-T Cells as Approaches to Kill Cancer Cells. Antibodies. 2019; 8:41.
  4. Wu Y, et al. HLA-A2-Restricted Epitopes Identified from MTA1 Could Elicit Antigen-Specific Cytotoxic T Lymphocyte Response. Journal of Immunology Research. 2018; Article ID 2942679.
  5. https://clinicaltrials.gov/ct2/show/NCT04272203. Accessed November 2020.

Non-Small Cell Lung Cancer (NSCLC)

  1. Souers AJ, Leverson JD, Boghaert ER, et al. ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets. Nat Med. 2013;19(2):202-208.
  2. Tse C, Shoemaker AR, Adickes J, et al. ABT-263: a potent and orally bioavailable Bcl-2 family inhibitor. Cancer Res. 2008;68(9):3421-3428.
  3. Waibel M, Solomon VS, Knight DA, 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.
  4. Zhang M, Mathews Griner LA, Ju W, 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.
  5. McDaniel KF, Wang L, Soltwedel T, et al. Discovery of N-(4-(2,4-Difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl) ethanesulfonamide (ABBV-075/Mivebresib), a potent and orally available bromodomain and extraterminal domain (BET) family bromodomain inhibitor. J Med Chem. 2017;60(20):8369-8384.
  6. 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.
  7. 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.
  8. Anders CK, Winer EP, Ford JM, et al. Poly(ADP-ribose) polymerase inhibition: "targeted" therapy for triple-negative breast cancer. Clin Cancer Res. 2010;16(19):4702-4710.
  9. Plummer ER, Calvert H. Targeting poly(ADP-ribose) polymerase: a two-armed strategy for cancer therapy. Clin Cancer Res. 2007;13(21):6252-6256.
  10. 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.
  11. 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.
  12. 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]
  13. 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.
  14. Saunders LR, Bankovich AJ, Anderson WC, et al. A DLL3-targeted antibody-drug conjugate eradicates high-grade pulmonary neuroendocrine tumor-initiating cells in vivo. Sci Transl Med. 2015;7(302):302ra136.
  15. 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.
  16. Phillips AC, Boghaert ER, Vaidya KS, et al. ABT-414, an antibody-drug conjugate targeting a tumor-selective EGFR epitope. Mol Cancer Ther. 2016(4):661-669.
  17. Reynolds, PA, Smolen GA, Palmer RE, et al. Identification of a DNA-binding site and transcriptional target for the EWS-WT1(+KTS) oncoprotein. Genes Dev. 2003;17(17):2094-2107.
  18. Li Y, Hickson J, Ambrosi D, et al. ABT-165 is a first-in-class therapeutic dual variable domain immunoglobulin (DVD-IgTM) that targets DLL4 and VEGF for the treatment of cancer. Proceedings of the AACR, Part A: Abstracts 1-2696. 2016;57:abstract 867.
  19. Tortorella S, Karagiannis TC. Transferrin receptor-mediated endocytosis: a useful target for cancer therapy. J Membr Biol. 2014;247(4):291-307.
  20. Xu Y, Vakoc CR. Targeting cancer cells with BET bromodomain inhibitors. Cold Spring Harb Perspect Med. 2017;7(7):a026674.
  21. Delmore JE, Issa GC, Lemieux ME, et al. BET bromodomain inhibition as a therapeutic strategy to target c-Myc. Cell. 2011;146(6):904-917.
  22. Gan HK, Cvrljevic AN, Johns TG. The epidermal growth factor receptor variant III (EGFRvIII): where wild things are altered. FEBS J. 2013;280(21):5350-5370.
  23. Brennan CW, Verhaak RG, McKenna A, et al. The somatic genomic landscape of glioblastoma. Cell. 2013;155(2):462-477.
  24. Ostrom QT, Gittleman H, Fulop J, et al. CBTRUS statistical report: primary brain and central nervous system tumors diagnosed in the United States in 2008-2012. Neuro Oncol. 2015;17 Suppl 4:iv1-iv62.
  25. Ren YR, Patel K, Paun BC, Kern SE. Structural analysis of the cancer-specific promoter in mesothelin and in other genes overexpressed in cancers. J Biol Chem. 2011;286(14):11960-11969.
  26. Pastan I, Hassan R. Discovery of mesothelin and exploiting it as a target for immunotherapy. Cancer Res. 2014;74(11):2907-2912.
  27. Ordóñez NG. Application of mesothelin immunostaining in tumor diagnosis. Am J Surg Pathol. 2003;27(11):1418-1428.
  28. Hassan R, Laszik ZG, Lerner M, Raffeld M, Postier R, Brackett D. Mesothelin is overexpressed in pancreaticobiliary adenocarcinomas but not in normal pancreas and chronic pancreatitis. Am J Clin Pathol. 2005;124(6):838-845.
  29. Argani P, Iacobuzio-Donahue C, Ryu B, et al. Mesothelin is overexpressed in the vast majority of ductal adenocarcinomas of the pancreas: identification of a new pancreatic cancer marker by serial analysis of gene expression (SAGE). Clin Cancer Res. 2001;7(12):3862-3868.
  30. Servais EL, Colovos C, Rodriguez L, et al. Mesothelin overexpression promotes mesothelioma cell invasion and MMP-9 secretion in an orthotopic mouse model and in epithelioid pleural mesothelioma patients. Clin Can Res. 2012;18(9):2478-2489.
  31. Ordóñez NG. The immunohistochemical diagnosis of mesothelioma: a comparative study of epithelioid mesothelioma and lung adenocarcinoma. Am J Surg Pathol. 2003;27(8):1031-1051.
  32. Kachala SS, Bograd AJ, Villena-Vargas J, et al. Mesothelin overexpression is a marker of tumor aggressiveness and is associated with reduced recurrence-free and overall survival in early-stage lung adenocarcinoma. Clin Cancer Res. 2014;20(4):1020-1028.
  33. Tozbikian G, Brogi E, Kadota K, et al. Mesothelin expression in triple negative breast carcinomas correlates significantly with basal-like phenotype, distant metastases and decreased survival. PLoS One. 2014;9(12):e114900.
  34. Tchou J, Wang LC, Selven B, et al. Mesothelin, a novel immunotherapy target for triple negative breast cancer. Breast Cancer Res Treat. 2012;133(2):799-804.
  35. van Kooten C, Banchereau J. CD40-CD40 ligand. J Leukoc Biol. 2000;67(1):2-17.
  36. 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.
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