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Chronic lymphocytic leukemia (CLL) is a disease that shows the progressive accumulation of mature B cells in the blood, lymph nodes, spleen, and bone marrow. There are too many blood stem cells that become abnormal lymphocytes and cannot go on to become healthy white blood cells that will correctly fight infection. There are five crucial treatments currently for CLL. They include watchful waiting, radiation, chemotherapy, surgery to remove the spleen, and targeted therapy. Target therapies include monoclonal antibody therapy where an antibody is made in the lab from a single immune cell. This antibody is targeted to bind substances either on the cancer cell or substances found in the body (https://www.cancer.gov/types/leukemia/patient/cll-treatment-pdq).
Ofatumumab is an approved, fully human, anti-CD20 IgG1κ monoclonal antibody (1). Ofatumumab induces killing of tumor B-cell lines and primary tumor cells via activation of complement-dependent cytotoxicity (CDC) and antibody-dependent cell-mediated cytotoxicity (ADCC). CD20 is part of the MS4A family of proteins and is expressed in both malignant and normal B cells. This protein helps in the proliferation and survival of B cells (2). CD20 appears to be the ideal target in certain white blood cell cancers.CD20 is highly expressed in the plasma membrane of almost all B cells, but not hematological stem cells or plasma cells. This protein usually remains at the cell surface even after cross-linking with monoclonal antibodies. It is never removed from the surface to block binding by monoclonal antibodies. These properties make CD20 a perfect target for monoclonal antibody treatment and allow efﬁcient effector recruitment for ADCC and CDC (3).
Complement is part of the innate immune response to destroy cells that are infected by a pathogen or just not working the way they should be working. CDC is part of complement and works to kill cells infected with pathogens by damaging the cell membrane usually via membrane attack complex (MAC). Baig et al. concluded that ofatumumab activates complement in the circulation of CLL patients and promotes lysis and elimination of opsonized cells. The removal of these cells will result in a substantial decrease in circulating CLL cells in most patients. After administration of the initial large dose of ofatumumab, the CLL cells that are still circulating are subjected to trogocytosis, which happens when lymphocytes conjugate to antigen presenting cells and extract surface molecules and express them. This will allow lymphocytes to express antigen presenting cell molecules on their surface. These lymphocytes, mainly B cells, in this case, will have deficient levels of CD20 expression since they are presenting surface molecules from other cells. Since CD20 levels have decreased, the response to ofatumumab will also decrease. The reduced binding suggests that the first dose of OFA has exceeded the maximum capacity of monoclonal antibody-mediated cytotoxic mechanisms. They hypothesized that maybe a lower dose of ofatumumab administered more frequently should be evaluated in future research to test the efficacy of this drug (4). Replacement of complement factor H was then seen to increase the susceptibility of CLL cells to ofatumumab. Horl et al. replaced factor H with short consensus repeat to enhance CDC. Factor H works to protect CLL cells against complement, so they believed that by replacing factor H nothing would be there to stop complement from happening. These short repeats were able to overcome complement resistance occurring during treatment with ofatumumab alone (5).
Ofatumumab has been tested as a single agent in many different types of presentation of CLL. Research is done in both untreated CLL patients as well as CLL that has relapsed after another drug or treatment has been used. Many different doses were tested in each setting. Monoclonal antibody treatment is dependent on complement activation and subsequent CDC. Coiffier et al. performed research in vitro to compare ofatumumab and rituximab. Ofatumumab can lyse Rituximab, which was another monoclonal antibody treatment that still showed disease progression, resistant Raji cells which express low levels of CD20 and higher levels of complement-regulatory protein CD55. Ofatumumab was well tolerated in doses up to 2000 mg in patients who had relapsed or refractory CLL. It was observed that ofatumumab targeted a different epitope of the CD20 molecule and this was correlated with its CDC activity (1).
Treatment of CLL with Fludarabine, a chemotherapy drug, showed disease progression. Weirda et al. studied patients who were treated with this chemotherapy drug and are now treating with ofatumumab. The treatment was associated with considerable relief of CLL symptoms. Some of these symptoms that were resolved include splenomegaly and hepatomegaly. These results were also seen even if that patient had been treated with both fludarabine and rituximab previously (6). Patients with untreated CLL had a higher success rate than patients who only were treated with rituximab. Rituximab was seen to work via the ADCC pathway mainly, and ofatumumab works primarily via the CDC pathway. Ofatumumab was designed to bind a different epitope of CD20 that is found closer to the cell membrane than rituximab so it can start a stronger CDC. Ofatumumab was seen to activate the highest degree of complement and attract macrophages to phagocytize the infected B-cells. (7).
Three major treatment groups have been combined with ofatumumab in patients with CLL. They are chemotherapy, Bruton’s tyrosine kinase (BTK) inhibitors, and immunomodulatory agents. Ofatumumab is used along with Lenalidomide which is an immunomodulatory agent that exerts both direct antitumor effects and pleiotropic activity on the immune system. Patients in this study suffered from relapsed or refractory CLL. Vitale et al. researched the impact of Lenalidomide and ofatumumab since both have interesting effects on the immune system. Many biological studies were performed including effects on T-cells and natural killer cells, angiogenic mediators and levels of select cytokines and chemokines. This combination seemed to be well tolerated in patients with relapsed or refractory CLL and even showed some patients who achieved remission (8). Research was done to see if ofatumumab with bendamustine or ofatumumab with fludarabine/cyclophosphamide should proceed to a phase III trial. The trial was a clinical study done on patients that had relapsed CLL. There are two different dose amounts of each chemotherapy-ofatumumab combination to see if larger doses would be better or if smaller doses would be enough. (9). Bruton Tyrosine Kinase (BTK), a member of the Tec kinase family, plays a role in the activation of downstream signaling required for survival and proliferation of malignant B cells. An inhibitor of this activation was tested with Ofatumumab in CLL patients. Ibrutinib was the inhibitor that was tested. It is orally administered and induces apoptosis of CLL cells and inhibited migration to the tumor microenvironment. Three different doses were administered, and all of them showed high clinical activity but some time-limited neuropathy. Future studies will have to not only look at Ibrutinib activity with a monoclonal antibody but will also have to asses toxicity (10). Another combination was observed between ofatumumab and alemtuzumab. Ofatumumab had significantly increased complement activation and CDC in alemtuzumab-treated CLL cells in vitro. Complement factor C3b, which aids in CDC had increased deposition on cells treated with both Alemtuzumab and ofatumumab than it did in either drug on its own. Baig et al. did find some resistance in cells to activated complement which may be proposed that this in vitro test may have different results in vivo depending on the patient and their immune system (11).
In addition to CLL, ofatumumab has been tested using patients with other white blood cell cancers, like non-Hodgkins lymphoma, as well as nephrotic syndrome and multiple sclerosis. Some testing has been done on non-Hodgkins lymphoma, which tends to express more CD20 on cell surfaces than CLL. Cell lines in serum at low and physiological concentrations were used to compare CDC availability in non-Hodgkins lymphoma with both ofatumumab and rituximab. Okroj et al. showed what other studies have found, that ofatumumab is better at activating CDC than rituximab (12). Nephrotic syndrome in children is a kidney disease where the body excretes too much protein in the urine. nephrotic syndrome is the most common chronic glomerular disease in children. Immunosuppressive therapies are given but usually lead to steroid dependence. Rituximab was used as a treatment for nephrotic syndrome since it targets B- cells. It was first thought that nephrotic syndrome was caused by T-cell functions, but it may actually be caused by B cell-derived factors, including B cell cytokines and autoantibodies (13). Some resistance was observed with rituximab in treatment since ofatumumab has been proven to attack B-cells better it was given as a treatment in rituximab-resistant nephrotic syndrome. The patients in this trial had better luck with ofatumumab as a treatment for pediatric nephrotic syndrome, but more research will need to be done since it is still unclear how nephrotic syndrome happens (14). Multiple sclerosis is a chronic inflammatory demyelinating disease that is caused by an autoimmune response. This response affects the central nervous system. Traditionally considered a T-cell-mediated disorder, the influence of B cells to the pathogenesis of multiple sclerosis has long been debated. Bittner et al. performed a placebo-controlled phase I and phase II trial in 38 patients with multiple sclerosis. After treatment with ofatumumab at different doses, a significant reduction of lesions in the central white matter of the central nervous system was observed after 24 weeks in all doses. Treatment did not show any alarming health concerns and was generally well tolerated. Phase III trials will be part of future studies involving ofatumumab and multiple sclerosis (15).
Ofatumumab is an incredible monoclonal antibody treatment that is now FDA approved for the treatment of CLL. Many ongoing studies are currently being researched in both treated and untreated cases of white blood cell cancers along with diseases, such as nephrotic syndrome and multiple sclerosis, that can be caused by B-cells. Monoclonal antibodies are always being researched in order to find the best treatment for a disease. Ofatumumab has demonstrated to be well tolerated in both single-use and combination therapy. In vitro testing have been seen to have better results than in vivo testing since patients will all have different levels of receptors and complement factors, but this is something that can hopefully be researched more. Since ofatumumab is one of the first fully human monoclonal antibody on the market hopefully future outlooks for more fully, human antibody treatments can also be approved as treatments.
- Coiffier B., Lepretre S., Pedersen L., Gadeberg O., Fredriksen H., van Oers M., et al. 2008. Safety and efficacy ofatumumab, a fully human monoclonal anti-CD20 antibody, in patients with relapsed or refractory B-cell chronic lymphocytic leukemia: a phase 1–2 study. Blood. 111(1):1094–1100.
- Parham, P. (2015) The Immune System. New York, New York: Garland Science.
- Teeling J., Mackus W., Wiegman L., van den Brakel J., Beers S., French R., et al. 2006. The biological activity of human CD20 monoclonal antibodies is linked to unique epitopes on CD20. Journal of Immunology. 177(1):362–371
- Baig, N., Taylor, R., Lindorfer, M., Church, A., LaPlant, B., Pettinger, A., Shanafelt, T., et al. 2014. Induced resistance to ofatumumab-mediated cell clearance mechanisms, including complement-dependent cytotoxicity, in chronic lymphocytic leukemia. Journal of Immunology. 192(4):1620-1629.
- Hörl, S., Banki, Z., Huber, G., Ejaz, A., Müllauer, B., Willenbacher, E., et al. 2013. Complement factor H-derived short consensus repeat 18-20 enhanced complement-dependent cytotoxicity of ofatumumab on chronic lymphocytic leukemia cells. Haematologica. 98(12):1939-1947.
- Wierda, W., Kipps, T., Mayer, J., Stilgenbauer, S., Williams, C., Hellmann, A., et al. 2010. Ofatumumab as single-agent CD20 immunotherapy in fludarabine-refractory chronic lymphocytic leukemia. Journal of Clinical Oncology. 28(10):1749-1755.
- Shanafelt, T., Lanasa, M., Call, T., Beaven, A., Leis, J., LaPlant, B., et al. 2013. Ofatumumab-based chemoimmunotherapy is effective and well tolerated in patients with previously untreated chronic lymphocytic leukemia (CLL). Cancer, 119(21):3788-3796.
- Vitale, C., Falchi, L., Ten Hacken, E., Gao, H., Shaim, H., Van Roosbroeck, K., et al. 2016. Ofatumumab and Lenalidomide for Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia: Correlation between Responses and Immune Characteristics. Clinical Cancer Research. 22(10):2359-2367.
- Howard, D., Munir, T., Hockaday, A., Rawstron, A., Collett, L., Oughton, J., et al. 2016. Chemotherapy plus Ofatumumab at Standard or Mega dose in relapsed CLL (COSMIC) trial: study protocol for a phase II randomised controlled trial. Trials, 17(1):1-11.
- Jaglowski, S., Jones, J., Nagar, V., Flynn, J., Andritsos, L., Maddocks, K., et al. 2015. Safety and activity of BTK inhibitor ibrutinib combined with ofatumumab in chronic lymphocytic leukemia: a phase 1b/2 study. Blood, 126(7):842-850.
- Baig, N., Taylor, R., Lindorfer, M., Church, A., Laplant, B., Pavey, E., et al. 2012. Complement dependent cytotoxicity in chronic lymphocytic leukemia: ofatumumab enhances alemtuzumab complement dependent cytotoxicity and reveals cells resistant to activated complement. Leukemia & lymphoma, 53(11):2218-2227.
- Okroj M., Eriksson I., Osterborg A., Blom A., 2013. Killing of CLL and NHL cells by rituximab and ofatumumab under limited availability of complement. Journal of Medical Oncology. 30(4):1-8.
- Iijima, K., Sako, M., & Nozu, K. 2016. Rituximab for nephrotic syndrome in children. Clinical and experimental nephrology, 21(2), 193-202.
- Wang, C., Liverman, R., Garro, R., George, R., Glumova, A., Karp, A., 2017. Ofatumumab for the treatment of childhood nephrotic syndrome. Pediatric nephrology. 32(5), 835-841.
- Bittner, S., Ruck, T., Wiendl, H., Grauer, O., Meuth, S. 2016. Targeting B cells in relapsing-remitting multiple sclerosis: from pathophysiology to optimal clinical management. Therapeutic advances in neurological disorders, 10(1), 51-66.
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