Lenzilumab
Monoclonal antibody | |
---|---|
Type | Whole antibody |
Source | Human |
Target | human colony stimulating factor 2 |
Clinical data | |
Other names | KB003 |
ATC code |
|
Identifiers | |
CAS Number | |
ChemSpider |
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UNII | |
KEGG | |
Chemical and physical data | |
Formula | C6474H10024N1748O2010S42 |
Molar mass | 145852.15 g·mol−1 |
Lenzilumab (
GM-CSF
).
Pre-clinical evidence and clinical data implicate GM-CSF as a crucial initiator in the systemic inflammatory pathway driving the serious and life-threatening
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
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
References
- ^ "Lenzilumab - AdisInsight". adisinsight.springer.com. Retrieved 2017-03-24.
- ^ "Anti-Human CSF2 Therapeutic Antibody (lenzilumab) - Creative Biolabs". www.creativebiolabs.net. Retrieved 2017-03-24.
- PMID 26341401.
- PMID 18089573.
- PMID 27849169.
- PMID 30463995.
- ^ "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.
- PMID 31585949.
- PMID 31880771.
- PMID 30487251.
- ^ "Humanigen Pipeline". Humanigen. 2020.
- PMID 31986264.
- ^ "Humanigen Submits Phase III Protocol Synopsis to FDA for Lenzilumab for Coronavirus Treatment". Bloomberg. 2020.
- ^ "Lenzilumab :: KaloBios Pharmaceuticals, Inc. (KBIO)". KaloBios Pharmaceuticals, Inc. Archived from the original on 2017-03-22. Retrieved 2017-03-24.
- ^ Statement On A Nonproprietary Name Adopted By The USAN Council - Lenzilumab, American Medical Association.
- ^ World Health Organization (2014). "International Nonproprietary Names for Pharmaceutical Substances (INN). Proposed INN: List 111" (PDF). WHO Drug Information. 28 (2).
- PMID 23632888.
- ^ "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.
- ^ Clinical trial number NCT02546284 for "Study of Lenzilumab (KB003) in Previously Treated Patients With Chronic Myelomonocytic Leukemia (CMML)" at ClinicalTrials.gov
- ^ Clinical trial number NCT01603277 for "Effect of KB003 in Subjects With Asthma Inadequately Controlled by Corticosteroids" at ClinicalTrials.gov
- ^ Clinical trial number NCT00995449 for "Study of KB003 In Biologics-Inadequate Rheumatoid Arthritis" at ClinicalTrials.gov
- ^ Clinical trial number NCT04583969 at ClinicalTrials.gov
- ^ "NIH study aims to identify promising COVID-19 treatments for larger clinical trials". 13 October 2020.