Lenzilumab

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).

Lenzilumab
Monoclonal antibody
TypeWhole antibody
SourceHuman
Targethuman colony stimulating factor 2
Clinical data
Other namesKB003
ATC code
  • none
Identifiers
CAS Number
ChemSpider
  • none
UNII
KEGG
Chemical and physical data
FormulaC6474H10024N1748O2010S42
Molar mass145852.15 g·mol−1

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. Another study found GM-CSF secreting CD8+ and CD4+ T-cells were higher in peripheral blood of ICU admitted patients in comparison to non-ICU admitted patients.[13] This correlated with a greater percentage of inflammatory monocytes and IL-6 secretion in peripheral blood. It is hypothesized soluble GM-CSF blockade with Lenzilumab may dampen down myeloid cell recruitment and inflammatory cytokine production, thus reducing the incidence and severity of ARDS. A Phase III protocol for evaluating the efficacy of Lenzilumab in the prevention and treatment of ARDS has been submitted to the FDA.[14]

Lenzilumab is under development by Humanigen Inc. and was originally designed for the treatment of chronic myelomonocytic leukemia (CMML) and juvenile myelomonocytic leukemia (JMML).[15][16][17] 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.[18] As of 2017, Lenzilumab is currently undergoing clinical trials for CMML.[19][20] Prior to application in treating CMML, Lenzilumab was assessed for use in treating inadequately controlled asthma[21] and rheumatoid arthritis.[22]

Covid-19

The NIH has chosen lenzilumab for its ACTIV-5 Big Effect trial.[23] [24]

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". Gilead Sciences Inc. Press Release.
  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. Zhou Y, et al. (2020). "Pathogenic T cells and inflammatory monocytes incite inflammatory storm in severe COVID-19 patients". Perspective Immunology (Preprint).
  14. "Humanigen Submits Phase III Protocol Synopsis to FDA for Lenzilumab for Coronavirus Treatment". Bloomberg. 2020.
  15. "Lenzilumab :: KaloBios Pharmaceuticals, Inc. (KBIO)". KaloBios Pharmaceuticals, Inc. Retrieved 2017-03-24.
  16. Statement On A Nonproprietary Name Adopted By The USAN Council - Lenzilumab, American Medical Association.
  17. World Health Organization (2014). "International Nonproprietary Names for Pharmaceutical Substances (INN). Proposed INN: List 111" (PDF). WHO Drug Information. 28 (2).
  18. 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.
  19. "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.
  20. Clinical trial number NCT02546284 for "Study of Lenzilumab (KB003) in Previously Treated Patients With Chronic Myelomonocytic Leukemia (CMML)" at ClinicalTrials.gov
  21. Clinical trial number NCT01603277 for "Effect of KB003 in Subjects With Asthma Inadequately Controlled by Corticosteroids" at ClinicalTrials.gov
  22. Clinical trial number NCT00995449 for "Study of KB003 In Biologics-Inadequate Rheumatoid Arthritis" at ClinicalTrials.gov
  23. Clinical trial number NCT04583969 at ClinicalTrials.gov
  24. https://www.nih.gov/news-events/news-releases/nih-study-aims-identify-promising-covid-19-treatments-larger-clinical-trials
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