Topic: Find me a mAB!

Essay Title: The Cleaving Process of Crizanlizumab!

(Submitted October 3rd, 2025)

Sickle cell disease (SCD) remains one of the most pervasive inherited blood disorders in the United States, disproportionately affecting African Americans. According to the Center for Disease Control, around 1 in 365 Black or African American newborns are estimated to be born with SCD (which also constitutes around 1 in 16,300 Hispanic births). Moreover, it is estimated that roughly 100,000 people in the U.S. live with SCD, with more than 90% of them identifying as non-Hispanic Black. (Control, 2024) The destructive nature of SCD lies in its capacity to damage multiple organ systems over a lifetime: recurrent vaso-occlusive pain crises, chronic hemolytic anemia, risk of stroke, pulmonary hypertension, chronic kidney disease, and susceptibility to infections due to functional asplenia.

At the heart of SCD is a mutation in the β-globin subunit gene (HBB) leading to hemoglobin S (HbS). Under deoxygenated conditions, HbS molecules polymerize, distorting red blood cells (RBCs) into a crescent, sickle-like shape. These deformed, rigid RBCs have impaired deformability and increased tendency to adhere to endothelium, causing microvascular obstruction, ischemia, and tissue damage (Lu et al., 2021) In normal RBCs with wild-type hemoglobin A (HbA), the biconcave disc shape and membrane flexibility permit passage through capillaries and the efficient transfer of oxygen and carbon dioxide throughout the body, as well as maintenance of ionic balance and membrane integrity (through procedures such as ATP-driven ion pumps & deformability stress responses).

When RBCs repeatedly sickle and recover, cumulative damage to the membrane and cytoskeleton can lead to irreversible sickling, increased hemolysis, and reduced lifespan of RBCs (often to only 10–20 days). The release of free hemoglobin, heme, and other byproducts induces oxidative stress, endothelial activation, nitric oxide scavenging, and inflammation, and coagulation cascades. More recent studies have observed that non-sickled RBCs and other blood elements (e.g. leukocytes, platelets) can become involved indirectly: for example, RBC-derived microparticles and complement activation contribute to endothelial injury and propagate a chronic inflammatory milieu in SCD patients. (Nader et al., 2020).

One promising therapeutic advance in SCD is crizanlizumab, a humanized monoclonal antibody approved in 2019 (marketed as Adakveo) for reducing the frequency of vaso-occlusive crises (VOCs) in SCD patients aged 16 years or older. (Administration, 2019). Crizanlizumab belongs to the IgG2 (kappa) subclass of immunoglobins. Its principal mechanism of action is binding to P-selectin (expressed on activated endothelial cells and platelets), thereby blocking the interaction with P-selectin glycoprotein ligand-1 (PSGL-1) on leukocytes, RBCs, and other blood cells. (Stevens et al., 2021) By doing so, crizanlizumab interferes with cell–cell adhesion cascades that contribute to vaso-occlusion — specifically, it reduces the tendency of sickled RBCs, leukocytes, and platelets to adhere to the endothelium under flow, thereby improving microvascular flow and reducing the incidence of occlusive events. (Karki & Kutlar, 2021)

Recent studies continue to refine our understanding of its efficacy. For instance, a 2025 analysis of the STAND (crizanlizumab with or without hydroxyurea) trial confirmed that crizanlizumab sustains P-selectin inhibition and is well tolerated, with fewer VOCs requiring medical visits in treated patients compared to placebo (Abboud et al., 2025). Similarly, a 2024 report also affirmed benefits of crizanlizumab in attenuating VOC frequency and lowering opioid use irrespective of SCD genotype or prior hydroxyurea therapy (DeBonnett et al., 2025).

In summary, crizanlizumab’s “cleaving” wherein it exhibits adhesive interactions mediated by P-selectin – is a rational and effective adjunctive therapy in SCD, particularly for reducing vaso-occlusive crises. By binding to P-selectin on endothelial and platelet surfaces, it impedes the adhesion of sickled RBCs, leukocytes, and platelets to the vascular wall, thereby reducing microvascular blockade and pain episodes. While it does not correct the underlying hemoglobin polymerization or fully reverse hemolysis, evidence from both in vitro investigations and real-world cohort studies support its safety and prophylactic benefit. Trending research is now investigating combination regimens (e.g. crizanlizumab combined with hydroxyurea or novel hemoglobin modulators), as well as exploring biomarkers (e.g. soluble P-selectin levels, microparticles) to serve as more effective responders to SCD. As gene therapies and next-generation biologics evolve, crizanlizumab remains a meaningful targeted therapy in the SCD armamentarium, especially for patients who continue to suffer recurrent VOCs despite standard care.

WORKS CITED

Abboud, M. R., Cançado, R. D., De Montalembert, M., Smith, W. R., Rimawi, H., Voskaridou, E., Güvenç, B., Ataga, K. I., Keefe, D., Grosch, K., Watson, J., Reshetnyak, E., Nassin, M. L., & Dei-Adomakoh, Y. (2025). Crizanlizumab with or without hydroxyurea in patients with sickle cell disease (STAND): primary analyses from a placebo-controlled, randomised, double-blind, phase 3 trial. The Lancet Haematology, 12(4), e248-e257. https://doi.org/https://doi.org/10.1016/S2352-3026(24)00384-3

Administration, U. S. F. D. (2019). FDA approves crizanlizumab-tmca for sickle cell disease. U.S. Food & Drug Administration. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-crizanlizumab-tmca-sickle-cell-disease?utm_source=chatgpt.com

Control, C. f. D. (2024). Data and Statistics on Sickle Cell Disease. Center for Disease Control. https://www.cdc.gov/sickle-cell/data/index.html?utm_source=chatgpt.com

DeBonnett, L., Joshi, V., Silva-Pinto, A. C., Colombatti, R., Pasanisi, A., Arcioni, F., Cançado, R. D., Sarp, S., Sarkar, R., & Soliman, W. (2025). Real-World Evidence of Crizanlizumab Showing Reductions in Vaso-Occlusive Crises and Opioid Usage in Sickle Cell Disease. Eur J Haematol, 114(2), 293-302. https://doi.org/10.1111/ejh.14323

Karki, N. R., & Kutlar, A. (2021). P-Selectin Blockade in the Treatment of Painful Vaso-Occlusive Crises in Sickle Cell Disease: A Spotlight on Crizanlizumab. J Pain Res, 14, 849-856. https://doi.org/10.2147/jpr.S278285

Lu, M., Kanne, C. K., Reddington, R. C., Lezzar, D. L., Sheehan, V. A., & Shevkoplyas, S. S. (2021). Concurrent Assessment of Deformability and Adhesiveness of Sickle Red Blood Cells by Measuring Perfusion of an Adhesive Artificial Microvascular Network [Original Research]. Frontiers in Physiology, Volume 12 – 2021. https://doi.org/10.3389/fphys.2021.633080

Nader, E., Romana, M., & Connes, P. (2020). The Red Blood Cell-Inflammation Vicious Circle in Sickle Cell Disease. Front Immunol, 11, 454. https://doi.org/10.3389/fimmu.2020.00454

Stevens, D. L., Hix, M., & Gildon, B. L. (2021). Crizanlizumab for the Prevention of Vaso-Occlusive Pain Crises in Sickle Cell Disease. J Pharm Technol, 37(4), 209-215. https://doi.org/10.1177/87551225211008460