Invented by Matthew J. Bernett, Seung Yup Chu, John R. Desjarlais, Sher Bahadur Karki, Gregory Alan Lazar, Erik WeiKing Pong, John O. Richards, Eugene Alexander Zhukovsky, Xencor Inc
The Xencor Inc invention works as followsThe present invention describes CD19-targeting antibodies, which comprise at least one modification compared to a parent antigen, the modification altering affinity to an FcR or changing effector function compared to the parental antibody. The invention also discloses methods for using the antibodies.
Background for Optimized antibodies targeting CD19
B cells are lymphocytes which play an important role in humoral immunity. They are produced by the bone marrow in most mammals and make up 5-15% the circulating pool of lymphocytes. The primary function of B-cells is to produce antibodies against antigens. They are an important component of the adaptive immunity system.
The human body produces millions of B cells every day, which circulate in blood and lymphatic fluids to perform the function of immune surveillance. B cells (also known as B lymphocytes) do not produce antibodies before they are fully activated. The BCR is a receptor protein that is unique to each B cell. It will bind only to a specific antigen. It is the BCR, a membrane bound immunoglobulin molecule, that distinguishes B cells from all other lymphocyte types. This molecule is also the primary receptor for B-cell activation. After a B-cell encounters the cognate antigen, and receives a signal from a T-helper cell, it may differentiate further into one of the B-cell types listed below. The B cell can either directly become one of these types of cells or undergo an intermediate differentiation, the germinal centre reaction, in which the B cell hypermutates the variable region of the immunoglobulin genes and may undergo class switching.
The B-cell develops in several stages. Each stage represents a different change in the content of the genome at the antibody loci. The stages of B cell development include the Progenitor cells, Early B cells and Late B Cells, Large Pre B Cells, Small Pre B cells, Mature B Cells, and Immature cells.
The mature B cells are divided into four main types:
B-1 cells are CD5-expressing cells, a marker that is usually seen on T cells. B-1 cells express IgM more than IgG. They produce low affinity polyreactive anti-bodies found in serum, which are often specific to self-antigens and common bacterial polysaccharides. The lymph nodes, spleen, and B-1 cells are found in small numbers. They are more common in the peritoneal cavity and pleural cavity.
The conventional B-cells are called “B-2 cells” in most texts. They are found in the bone marrow and lymph nodes. When triggered by antigens, they may differentiate into IgG producing memory B cells. During these antibody responses, IgG can undergo significant affinity maturation.
Plasma cells” (also called plasma cells) are large, exposed B cells. They produce and secrete large quantities of antibodies that aid in the destruction and elimination of microbes through binding and facilitation by phagocytes as well activation of complement system. Plasma cells are often referred to “antibody factories”.
Memory B cells are made from B cells activated by the primary immune response and specific for the antigen. These cells can live a long period of time and respond quickly to a second encounter with the same antigen.
When a B-cell fails at any stage of maturation, it dies by a process called apoptosis. The B cell becomes suppressed or dies if it detects its own antigen during the maturation. B cells are produced continuously in the bone marrow. However, only a small percentage of these cells make it to the peripheral B-cell pools.
In recent years, it has been shown that B lymphocytes are more than just passive receptors of signals that lead to differentiation into plasma cells that produce antibodies. In addition to their traditional roles as antigen-presenting cells and precursors to antibody-producing cells, B-cells have been found to regulate the functions of antigen-presenting cells (APCs), T-cells, and produce cytokines. They also express receptor/ligand pair that were previously thought to be limited to other cell types.
Disregulation of B-cells is linked to a wide range of disorders because of their crucial role in the regulation of the immune system. B-cell disorders, also referred to herein as B-cell related diseases, are divided into excessive or uncontrolled proliferation (lymphomas, leukemias), and defects of B-cell development/immunoglobulin production (immunodeficiencies). Most (80%) lymphoma cases have B-cell origin. They include non-Hodgkin lymphoma, acute lymphoblastic lymphoma and autoimmune diseases.
NHL (a heterogeneous cancer) is a malignancy that originates from lymphocytes. In the United States, the incidence of NHL is estimated to be 65,000/year. Mortality is approximately 20,000 per year (American Cancer Society 2006; SEER Cancer Statistics Review). The disease can affect anyone, but the onset usually occurs in adults older than 40, and the incidence increases with age. NHL is characterized as a clonal proliferative lymphocyte accumulation in the lymph nodes and blood. It can also affect bone marrow, spleen or other major organs.
The diagnosis and histologic characterisation of NHL are made by combining morphologic and immunephenotype criteria. The World Health Organization’s Classification of Tumours is currently used by clinicians and pathologists to classify NHL. It divides it into B-cell and T-cell precursors and mature neoplasms. The PDQ currently divides NHL into indolent and aggressive NHL for entry into clinical trial. To maintain consistency, the current document will use a similar classification. Indolent NHL is composed primarily of small lymphocytic Lymphoma (SLL), MALT and marginal zone. It encompasses about 50% of newly diagnosed patients with B-cell NHL. Patients with aggressive NHL have histologic diagnoses that include diffuse large B-cell (40% of newly diagnosed patients are diffuse large cells), Burkitt?s and mantle cell.
The clinical course of NHL can be highly variable. The histologic type is a major factor in determining the clinical course. The most indolent forms of NHL are considered incurable. Most patients will respond to antibody or chemotherapy therapy initially, but most will experience a relapse. Early intervention has not been shown to improve survival in studies conducted so far. It is acceptable to “watch and wait” in asymptomatic cases. The patient must be symptomatic, or the pace of the disease appears to be increasing. The disease can change over time to become more aggressive. Indolent patients are often treated with 3 or more treatments in the course of their treatment. Combination chemotherapy has historically been the first treatment for symptomatic, indolent NHL patients. Most commonly used agents are cyclophosphamide vincristine prednisone, cyclophosphamide adriamycin vincristine prednisone, or fludarabine, which is a purine analog. About 70% to 80% will respond to the initial chemotherapy. Remissions can last up to 2-3 years. In the end, most patients will relapse. The anti-CD20 antigen, rituximab has been used in clinical trials to improve response rates and survival rates. Currently, the standard of care is rituximab+CHOP or rituximab+CVP for most patients. Interferon has been approved to treat NHL initially in combination with alkylating drugs, but its use is limited in the U.S.
Rituximab has shown efficacy in multiple types of NHL and is approved as the first-line treatment for both aggressive (diffuse B cell lymphoma), and indolent (follicular Lymphoma). There are some limitations to anti-CD20 monoclonal antibodies (mAbs), such as primary resistance (50 percent response rate for relapsed, indolent patients), acquisition resistance (50 percent response rate after re-treatment), and rare complete responses (2% response rate among relapsed populations). Many B-cell disorders cannot be treated with anti-CD20 antibodies because many B-cells do not express CD20. “Antibodies to antigens other CD20 could have anti-lymphoma properties that could overcome anti CD20 resistance or enhance the activity of anti CD20 therapy.
There are other types of leukemias, such as B-cell lymphoma. Chronic lymphocytic Leukemia, also known as “chronic lymphoid lymphoma” Chronic lymphocytic leukemia (also known as?chronic lymphoid leukemia? (also known as?CLL? CLL is characterized by malignant lymphocytes that may appear normal and mature but are unable to fight infection. CLL is the commonest form of adult leukemia. CLL is twice as common in men as it is in women. The main risk factor for CLL is age. More than 75% of all new cases are diagnosed among patients older than 50. “American Cancer Society (2006) and SEER Cancer Statistics Review” report that more than 10,000 new cases are diagnosed each year, with a mortality rate of almost 5,000 per year.
CLL is an incurable illness, but it progresses slowly for most people. CLL can be a chronic disease that is difficult to treat. However, many people who have CLL live normal lives and are active for years. Early-stage CLL, due to its slow onset is not generally treated. It is believed that treatment of CLL at this stage does not improve quality of life or survival. The condition is instead monitored over time. The initial CLL treatment varies depending on the diagnosis and progression of the illness. CLL is treated with dozens of different agents. Fludarabine, a purine analogue, was shown to have superior response rates compared with chlorambucil in primary therapy. However there is no evidence of a benefit from early fludarabine use. Fludarabine and cyclophosphamide regimens, FCR (fludarabine cyclophosphamide rituximab), and CHOP, are effective for both newly diagnosed and relapsed CLL. Due to the risks, allogeneic stem cell transplantation (allogeneic bone-marrow) is not used as first-line therapy for CLL.
?Refractory? “?Refractory? In such cases, more aggressive treatments, such as bone marrow transplantation (stem cells), are considered. “The monoclonal anti-CD52 antibody, alemtuzumab may be used by patients with refractory bone marrow disease.
Another type of leukemia, also called acute lymphocytic Leukemia, is acute lymphoblastic (ALL). ALL is characterized by an overproduction of immature and malignant white blood cells, also known as lymphoblasts, in the bone marrow. ?Acute? The term?acute? The disease is progressive and can be fatal if untreated. ALL is more common in children, with the peak incidence occurring between ages 4-5. It is more common in children aged 12-16. At least 80% childhood ALL is curable. “Under 4,000 cases of childhood ALL are diagnosed each year, and mortality is around 1,500 per year (American Cancer Society 2006; SEER Cancer Statistics Review).
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