Lenzilumab

Last updated
Lenzilumab
Monoclonal antibody
Type Whole antibody
Source Human
Target human colony stimulating factor 2
Clinical data
Other namesKB003
ATC code
  • none
Identifiers
CAS Number
ChemSpider
  • none
UNII
KEGG
Chemical and physical data
Formula C6474H10024N1748O2010S42
Molar mass 145852.15 g·mol−1

Lenzilumab (INN; development code KB003) [1] is a humanized monoclonal antibody (class IgG1 kappa) [2] that targets colony stimulating factor 2 (CSF2)/granulocyte-macrophage colony stimulating factor (GM-CSF).

Contents

Pre-clinical evidence and clinical data implicate GM-CSF as a crucial initiator in the systemic inflammatory pathway driving the serious and life-threatening chimeric antigen receptor T cell (CAR-T) associated cytokine release syndrome (CRS). GM-CSF is produced by CAR-T cells upon recognition of target cells, which activates myeloid cells and compels them to produce monocyte chemoattractant protein 1 (MCP-1) and its receptor (CCR2). [3] [4] GM-CSF knockout CAR-T cells protect mice from CRS; however, IL-6 knockout mice receiving wild-type CAR-T cells were not protected from CRS. [5] Moreover, mice infused with GM-CSF knockout CAR-T cells have significantly lower serum levels of MCP-1, IL-6, MIG, and MIP-1 than mice receiving wild-type CAR-T cells, demonstrating the role of GM-CSF signaling early in the inflammatory cascade. Administration of Lenzilumab in a patient-derived xenograft model significantly reduced CRS and neurotoxicity in mice, while preserving anti-leukemic efficacy. [6] A multi-center phase I/II trial including the MD Anderson Cancer Center will evaluate lenzilumab as prophylaxis for CRS and neurotoxicity in collaboration with Kite and is currently in recruitment. [7]

Additionally, GM-CSF has been shown to be instrumental in donor T-cell licensing of host and donor-derived myeloid cells in graft versus host disease (GVHD) following hematopoietic allotransplantation. [8] [9] Mice receiving allografts deficient in GM-CSF have significantly reduced incidence and severity of GVHD. [10] A Phase II study with the University of Zürich and the United Kingdom's Stem Cell Transplantation IMPACT group will be investigating the efficacy of lenzilumab in prevention of acute GVHD and is currently in active planning. [11]

In light of the recent coronavirus disease 2019 (COVID-19) pandemic, the role of GM-CSF in the cytokine-mediated immunopathology of lung injury and acute respiratory distress syndrome (ARDS) has been under investigation. Plasma of hospitalized patients with confirmed COVID-19 has elevated levels of several inflammatory cytokines including IL-1B, IL-2, GM-CSF, IFN-γ, IP-10, MCP-1, MIP-1A/B, TNFα, and VEGF, indicative of a cytokine storm. [12] Importantly, significantly higher levels of MCP-1, MIP-1A, and IP-10 (all of which are downstream of GM-CSF) were found to be significantly higher in ICU-admitted patients versus hospitalized but non-ICU admitted patients.[ citation needed ] A Phase III protocol for evaluating the efficacy of lenzilumab in the prevention and treatment of ARDS has been submitted to the FDA. [13]

Lenzilumab is under development by Humanigen Inc. and was originally designed for the treatment of chronic myelomonocytic leukemia (CMML) and juvenile myelomonocytic leukemia (JMML). [14] [15] [16] In vitro studies on human cells have demonstrated that Lenzilumab can induce sensitivity in myeloid and monocytic cells suggesting the antibody's applicability in CMML and JMML indications. [17] As of 2017, lenzilumab is currently undergoing clinical trials for CMML. [18] [19] Prior to application in treating CMML, lenzilumab was assessed for use in treating inadequately controlled asthma [20] and rheumatoid arthritis. [21]

Covid-19

The NIH has chosen lenzilumab for its ACTIV-5 Big Effect trial. [22] [23]

See also

Related Research Articles

<span class="mw-page-title-main">Monocyte</span> Subtype of leukocytes

Monocytes are a type of leukocyte or white blood cell. They are the largest type of leukocyte in blood and can differentiate into macrophages and monocyte-derived dendritic cells. As a part of the vertebrate innate immune system monocytes also influence adaptive immune responses and exert tissue repair functions. There are at least three subclasses of monocytes in human blood based on their phenotypic receptors.

In immunology, cytokine release syndrome (CRS) is a form of systemic inflammatory response syndrome (SIRS) that can be triggered by a variety of factors such as infections and certain drugs. It refers to cytokine storm syndromes (CSS) and occurs when large numbers of white blood cells are activated and release inflammatory cytokines, which in turn activate yet more white blood cells. CRS is also an adverse effect of some monoclonal antibody medications, as well as adoptive T-cell therapies. When occurring as a result of a medication, it is also known as an infusion reaction.

In biology, chimeric antigen receptors (CARs)—also known as chimeric immunoreceptors, chimeric T cell receptors or artificial T cell receptors—are receptor proteins that have been engineered to give T cells the new ability to target a specific antigen. The receptors are chimeric in that they combine both antigen-binding and T cell activating functions into a single receptor.

<span class="mw-page-title-main">Granulocyte-macrophage colony-stimulating factor</span> Mammalian protein found in Homo sapiens

Granulocyte-macrophage colony-stimulating factor (GM-CSF), also known as colony-stimulating factor 2 (CSF2), is a monomeric glycoprotein secreted by macrophages, T cells, mast cells, natural killer cells, endothelial cells and fibroblasts that functions as a cytokine. The pharmaceutical analogs of naturally occurring GM-CSF are called sargramostim and molgramostim.

<span class="mw-page-title-main">Interleukin 3</span> Protein-coding gene in the species Homo sapiens

Interleukin 3 (IL-3) is a protein that in humans is encoded by the IL3 gene localized on chromosome 5q31.1. Sometimes also called colony-stimulating factor, multi-CSF, mast cell growth factor, MULTI-CSF, MCGF; MGC79398, MGC79399: the protein contains 152 amino acids and its molecular weight is 17 kDa. IL-3 is produced as a monomer by activated T cells, monocytes/macrophages and stroma cells. The major function of IL-3 cytokine is to regulate the concentrations of various blood-cell types. It induces proliferation and differentiation in both early pluripotent stem cells and committed progenitors. It also has many more specific effects like the regeneration of platelets and potentially aids in early antibody isotype switching.

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Chronic myelomonocytic leukemia (CMML) is a type of leukemia, which are cancers of the blood-forming cells of the bone marrow. In adults, blood cells are formed in the bone marrow, by a process that is known as haematopoiesis. In CMML, there are increased numbers of monocytes and immature blood cells (blasts) in the peripheral blood and bone marrow, as well as abnormal looking cells (dysplasia) in at least one type of blood cell.

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References

  1. ↑ "Lenzilumab - AdisInsight". adisinsight.springer.com. Retrieved 2017-03-24.
  2. ↑ "Anti-Human CSF2 Therapeutic Antibody (lenzilumab) - Creative Biolabs". www.creativebiolabs.net. Retrieved 2017-03-24.
  3. ↑ Croxford AL, et al. (2015). "The Cytokine GM-CSF Drives the Inflammatory Signature of CCR2+ Monocytes and Licenses Autoimmunity". Immunity. 43 (3): 502–14. doi: 10.1016/j.immuni.2015.08.010 . PMID   26341401.
  4. ↑ Tanimoto A, et al. (2008). "Monocyte chemoattractant protein-1 expression is enhanced by granulocyte-macrophage colony-stimulating factor via Jak2-Stat5 signaling and inhibited by atorvastatin in human monocytic U937 cells". J. Biol. Chem. 283 (8): 4643–51. doi: 10.1074/jbc.M708853200 . PMID   18089573.
  5. ↑ Sentman ML, et al. (2016). "Mechanisms of Acute Toxicity in NKG2D Chimeric Antigen Receptor T Cell-Treated Mice". J. Immunol. 197 (12): 4674–4685. doi:10.4049/jimmunol.1600769. PMC   5136298 . PMID   27849169.
  6. ↑ Sterner RM, et al. (2019). "GM-CSF inhibition reduces cytokine release syndrome and neuroinflammation but enhances CAR-T cell function in xenografts". Blood. 133 (7): 697–709. doi:10.1182/blood-2018-10-881722. PMC   6376281 . PMID   30463995.
  7. ↑ "Kite and Humanigen Announce Clinical Collaboration to Evaluate Investigational Combination of Yescarta® (Axicabtagene Ciloleucel) with Lenzilumab in Relapsed/Refractory Diffuse Large B-Cell Lymphoma" (Press release). Gilead Sciences Inc.
  8. ↑ Gartlan KH, et al. (2019). "Donor T-cell–derived GM-CSF drives alloantigen presentation by dendritic cells in the gastrointestinal tract". Blood Advances. 3 (19): 2859–2865. doi:10.1182/bloodadvances.2019000053. PMC   6784518 . PMID   31585949.
  9. ↑ Piper C, et al. (2020). "Pathogenic Bhlhe40+ GM-CSF+ CD4+ T cells promote indirect alloantigen presentation in the GI tract during GVHD". Blood. 135 (8): 568–581. doi:10.1182/blood.2019001696. PMC   7033370 . PMID   31880771.
  10. ↑ Tugues S, et al. (2018). "Graft-versus-host disease, but not graft-versus-leukemia immunity, is mediated by GM-CSF-licensed myeloid cells". Science Translational Medicine. 10 (469): eaat8410. doi: 10.1126/scitranslmed.aat8410 . PMID   30487251.
  11. ↑ "Humanigen Pipeline". Humanigen. 2020.
  12. ↑ Huang C, et al. (2020). "Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China". The Lancet. 395 (10223): 497–506. doi:10.1016/S0140-6736(20)30183-5. PMC   7159299 . PMID   31986264.
  13. ↑ "Humanigen Submits Phase III Protocol Synopsis to FDA for Lenzilumab for Coronavirus Treatment". Bloomberg. 2020.
  14. ↑ "Lenzilumab :: KaloBios Pharmaceuticals, Inc. (KBIO)". KaloBios Pharmaceuticals, Inc. Archived from the original on 2017-03-22. Retrieved 2017-03-24.
  15. ↑ Statement On A Nonproprietary Name Adopted By The USAN Council - Lenzilumab, American Medical Association .
  16. ↑ World Health Organization (2014). "International Nonproprietary Names for Pharmaceutical Substances (INN). Proposed INN: List 111" (PDF). WHO Drug Information. 28 (2).
  17. ↑ Padron E, Painter JS, Kunigal S, Mailloux AW, McGraw K, McDaniel JM, Kim E, Bebbington C, Baer M, Yarranton G, Lancet J, Komrokji RS, Abdel-Wahab O, List AF, Epling-Burnette PK (June 2013). "GM-CSF-dependent pSTAT5 sensitivity is a feature with therapeutic potential in chronic myelomonocytic leukemia". Blood. 121 (25): 5068–77. doi:10.1182/blood-2012-10-460170. PMC   4347259 . PMID   23632888.
  18. ↑ "KaloBios Announces First Patient Dosed in Phase 1 Study of Lenzilumab for the Treatment of Chronic Myelomonocytic Leukemia". GlobeNewswire News Room. KaloBios Pharmaceuticals Inc. Retrieved 2017-03-24.
  19. ↑ Clinical trial number NCT02546284 for "Study of Lenzilumab (KB003) in Previously Treated Patients With Chronic Myelomonocytic Leukemia (CMML)" at ClinicalTrials.gov
  20. ↑ Clinical trial number NCT01603277 for "Effect of KB003 in Subjects With Asthma Inadequately Controlled by Corticosteroids" at ClinicalTrials.gov
  21. ↑ Clinical trial number NCT00995449 for "Study of KB003 In Biologics-Inadequate Rheumatoid Arthritis" at ClinicalTrials.gov
  22. ↑ Clinical trial number NCT04583969 at ClinicalTrials.gov
  23. ↑ "NIH study aims to identify promising COVID-19 treatments for larger clinical trials". 13 October 2020.
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