Ocaratuzumab

Last updated
Ocaratuzumab
Monoclonal antibody
Type ?
Source Humanized
Target CD20
Clinical data
ATC code
  • none
Identifiers
CAS Number
ChemSpider
  • none
UNII
KEGG
Chemical and physical data
Formula C6464H10016N1712O2010S44
Molar mass 145283.85 g·mol−1

Ocaratuzumab (AME-133v, LY2469298) is a humanized monoclonal antibody designed for the treatment of cancer and autoimmune disorders. [1] The antibody is engineered for enhanced affinity to the CD20 antigen on B-lymphocytes, increased antibody-dependent cell-mediated cytotoxicity (ADCC), and for improved treatment of low-affinity FcγRIIIa allotypes. [2]

Phase I/II trials in relapsed/refractory follicular lymphoma have been completed in the United States (US) and Japan, and a Phase I trial was conducted in US rheumatoid arthritis patients. [2] Phase III development in relapsed follicular lymphoma patients is underway. [3] Many patients relapse following currently available treatments, and a significant need for new effective treatment exists, particularly for patients with low-affinity FcγRIIIa allotypes. [4] In pre-clinical studies, ocaratuzumab was shown to have 13 to 20 fold greater affinity for CD20 and 6 fold more potent ADCC as compared to rituximab. [2] [4] Additional development in other oncology and rheumatology indications will also be pursued, as well as subcutaneous formations for patient convenience. [3]

This drug is currently being developed by Mentrik Biotech, LLC.

History

AME-133v is a humanized IgG1 monoclonal antibody targeting the CD20 antigen on both healthy and malignant B-lymphocytes, [2] engineered at Applied Molecular Evolution. Libraries of antibody Fab (fragment, antigen binding) regions were generated with codon substituted variations of the antibody complementarity determining regions (CDRs) inserted into human antibody light and heavy chain germline frameworks (data on file at Mentrik Biotec). Variants were expressed and selected based on increased binding affinity to CD20 (data on file at Mentrik Biotech). A variable region with increased binding activity for CD20 was selected and developed as AME-133v (data on file at Mentrik Biotech). AME-133v was purchased by Eli Lilly, received the name LY2469298, and a Phase I/II clinical trial in follicular lymphoma was conducted in the U.S. as well as a Phase I clinical trial in rheumatoid arthritis initiated in the U.S. (data shown below). [2] A Phase I clinical trial in follicular lymphoma was also conducted in Japan. [4] AME-133v was purchased by Mentrik, Biotech in 2011 and received the generic name ocaratuzumab from the United States Adopted Name Council in December 2011. [3]

Related Research Articles

Daclizumab is a therapeutic humanized monoclonal antibody which was used for the treatment of adults with relapsing forms of multiple sclerosis (MS). Daclizumab works by binding to CD25, the alpha subunit of the IL-2 receptor of T-cells.

<span class="mw-page-title-main">Rituximab</span> Pharmaceutical drug

Rituximab, sold under the brand name Rituxan among others, is a monoclonal antibody medication used to treat certain autoimmune diseases and types of cancer. It is used for non-Hodgkin lymphoma, chronic lymphocytic leukemia, rheumatoid arthritis, granulomatosis with polyangiitis, idiopathic thrombocytopenic purpura, pemphigus vulgaris, myasthenia gravis and Epstein–Barr virus-positive mucocutaneous ulcers. It is given by slow injection into a vein. Biosimilars of Rituxan include Blitzima, Riabni, Ritemvia, Rituenza, Rixathon, Ruxience, and Truxima.

<span class="mw-page-title-main">Cancer immunotherapy</span> Artificial stimulation of the immune system to treat cancer

Cancer immunotherapy is the stimulation of the immune system to treat cancer, improving on the immune system's natural ability to fight the disease. It is an application of the fundamental research of cancer immunology and a growing subspecialty of oncology.

<span class="mw-page-title-main">Ibritumomab tiuxetan</span> Radioimmunotherapy treatment

Ibritumomab tiuxetan, sold under the trade name Zevalin, is a monoclonal antibody radioimmunotherapy treatment for non-Hodgkin's lymphoma. The drug uses the monoclonal mouse IgG1 antibody ibritumomab in conjunction with the chelator tiuxetan, to which a radioactive isotope is added. Tiuxetan is a modified version of DTPA whose carbon backbone contains an isothiocyanatobenzyl and a methyl group.

<span class="mw-page-title-main">Diffuse large B-cell lymphoma</span> Type of blood cancer

Diffuse large B-cell lymphoma (DLBCL) is a cancer of B cells, a type of lymphocyte that is responsible for producing antibodies. It is the most common form of non-Hodgkin lymphoma among adults, with an annual incidence of 7–8 cases per 100,000 people per year in the US and UK. This cancer occurs primarily in older individuals, with a median age of diagnosis at ~70 years, although it can occur in young adults and, in rare cases, children. DLBCL can arise in virtually any part of the body and, depending on various factors, is often a very aggressive malignancy. The first sign of this illness is typically the observation of a rapidly growing mass or tissue infiltration that is sometimes associated with systemic B symptoms, e.g. fever, weight loss, and night sweats.

<span class="mw-page-title-main">Monoclonal antibody therapy</span> Form of immunotherapy

Monoclonal antibody therapy is a form of immunotherapy that uses monoclonal antibodies (mAbs) to bind monospecifically to certain cells or proteins. The objective is that this treatment will stimulate the patient's immune system to attack those cells. Alternatively, in radioimmunotherapy a radioactive dose localizes a target cell line, delivering lethal chemical doses. Antibodies have been used to bind to molecules involved in T-cell regulation to remove inhibitory pathways that block T-cell responses. This is known as immune checkpoint therapy.

Toralizumab was a humanized monoclonal antibody and an immunosuppressive drug. Possible indications included treatment of antibody-mediated disorders, T-cell-mediated diseases, and B-cell malignancies such as CLL/small lymphocytic lymphoma, follicular cell lymphoma grade I or II, marginal zone lymphoma, mantle cell lymphoma, MALT lymphoma, Waldenström's macroglobulinemia, monocytoid B-cell lymphoma; relapsed/refractory Hodgkin's disease).

Lintuzumab (SGN-33) is a humanized monoclonal antibody used in the treatment of cancer. The drug had been developed by Seattle Genetics as a treatment for acute myeloid leukemia (AML), a condition which results in the deaths of 9,000 people a year in the United States. Lintuzumab targets the CD33 protein, which is expressed in AML and other myeloproliferative diseases, but does not appear in abundance on normal cells.

Epratuzumab is a humanized monoclonal antibody. Potential uses may be found in oncology and in treatment of inflammatory autoimmune disorders, such as systemic lupus erythematosus (SLE).

<span class="mw-page-title-main">Ofatumumab</span>

Ofatumumab is a fully human monoclonal antibody to CD20, which appears to provide rapid B-cell depletion. Under the brand name Kesimpta, it is approved for the treatment of multiple sclerosis in the United States as well as in the European Union and other regions. Under the brand name Arzerra, it is approved for the treatment of certain types of chronic lymphocytic leukemia (CLL) in the United States. It is sold by Novartis under license from Genmab.

CD16, also known as FcγRIII, is a cluster of differentiation molecule found on the surface of natural killer cells, neutrophils, monocytes, macrophages, and certain T cells. CD16 has been identified as Fc receptors FcγRIIIa (CD16a) and FcγRIIIb (CD16b), which participate in signal transduction. The most well-researched membrane receptor implicated in triggering lysis by NK cells, CD16 is a molecule of the immunoglobulin superfamily (IgSF) involved in antibody-dependent cellular cytotoxicity (ADCC). It can be used to isolate populations of specific immune cells through fluorescent-activated cell sorting (FACS) or magnetic-activated cell sorting, using antibodies directed towards CD16.

An anti-CD22 immunotoxin is a monoclonal antibody linked to a cytotoxic agent. They are being studied in the treatment of some types of B-cell cancer.

Genmab A/S is a Danish biotechnology company, founded in February 1999 by Florian Schönharting, at the time managing director of BankInvest Biomedical venture fund. The company is based in Copenhagen, Denmark – internationally, it operates through the subsidiaries Genmab B.V. in Utrecht, The Netherlands, Genmab U.S., Inc. in Princeton, USA, and Genmab K.K. in Tokyo, Japan. It's a dual listed company with shares traded on the Copenhagen Stock Exchange in Denmark, and on NASDAQ Global Select Market in the US.

Obinutuzumab, sold under the brand name Gazyva among others, is a humanized anti-CD20 monoclonal antibody, originated by GlycArt Biotechnology AG and developed by Roche as a cancer treatment.

Atacicept is a recombinant fusion protein designed to inhibit B cells, thereby suppressing autoimmune disease. The designer protein combines the binding site for two cytokines that regulate maturation, function, and survival of B cells - B-lymphocyte stimulator (BLyS) and A proliferation-inducing ligand (APRIL), with the constant region of immunoglobin. Atacicept blocks activation of B cells by the tumor necrosis factor receptor superfamily member 13B, a transmembrane receptor protein found predominantly on the surface of B cells. Like the monoclonal antibody belimumab, atacicept blocks the binding of BLyS, but it also blocks APRIL. Binding of these TACI ligands induces proliferation, activation, and longevity of B cells and thus their production of autoantibodies. Atacicept is thought to selectively impair mature B cells and plasma cells with less impact on progenitor cells and memory B cells.

Gene expression profiling has revealed that diffuse large B-cell lymphoma (DLBCL) is composed of at least 3 different sub-groups, each having distinct oncogenic mechanisms that respond to therapies in different ways. Germinal Center B-Cell like (GCB) DLBCLs appear to arise from normal germinal center B cells, while Activated B-cell like (ABC) DLBCLs are thought to arise from postgerminal center B cells that are arrested during plasmacytic differentiation. The differences in gene expression between GCB DLBCL and ABC DLBCL are as vast as the differences between distinct types of leukemia, but these conditions have historically been grouped together and treated as the same disease.

Urelumab is a fully human, non‐ligand binding, CD137 agonist immunoglobulin‐γ 4 (IgG4) monoclonal antibody. It was developed utilizing Medarex's UltiMAb(R) technology by Bristol-Myers Squibb for the treatment of cancer and solid tumors. Urelumab promotes anti-tumor immunity, or an immune response against tumor cells, via CD137 activation. The application of Urelumab has been limited due to the fact that it can cause severe liver toxicity.

<span class="mw-page-title-main">Daratumumab</span>

Daratumumab, sold under the brand name Darzalex, is an anti-cancer monoclonal antibody medication. It binds to CD38, which is overexpressed in multiple myeloma cells. Daratumumab was originally developed by Genmab, but it is now being jointly developed by Genmab along with the Johnson & Johnson subsidiary Janssen Biotech, which acquired worldwide commercialization rights to the drug from Genmab.

Pidilizumab is a monoclonal antibody being developed by Medivation for the treatment of cancer and infectious diseases. Pidilizumab was originally thought to bind to the PD-1 immune checkpoint molecule, however, recent evidence suggests that Delta-like 1 (DLL1) is its primary binding target while binding to PD-1 is secondary and restricted to non-glycosylated and hypoglycosylated forms of this molecule. Pidilizumab causes in the attenuation of apoptotic processes in lymphocytes, primarily effector/memory T cells.

Seagen Inc. is an American biotechnology company focused on developing and commercializing innovative, empowered monoclonal antibody-based therapies for the treatment of cancer. The company, headquartered in Bothell, Washington, is the industry leader in antibody-drug conjugates or ADCs, a technology designed to harness the targeting ability of monoclonal antibodies to deliver cell-killing agents directly to cancer cells. Antibody-drug conjugates are intended to spare non-targeted cells and thus reduce many of the toxic effects of traditional chemotherapy, while potentially enhancing antitumor activity.

References

  1. "Statement On A Nonproprietary Name Adopted By The USAN Council - Ocaratuzumab" (PDF). American Medical Association.
  2. 1 2 3 4 5 Forero-Torres A, de Vos S, Pohlman BL, Pashkevich M, Cronier DM, Dang NH, et al. (March 2012). "Results of a phase 1 study of AME-133v (LY2469298), an Fc-engineered humanized monoclonal anti-CD20 antibody, in FcγRIIIa-genotyped patients with previously treated follicular lymphoma". Clinical Cancer Research. 18 (5): 1395–403. doi: 10.1158/1078-0432.CCR-11-0850 . PMID   22223529.
  3. 1 2 3 "mentrik.com".
  4. 1 2 3 Tobinai K, Ogura M, Kobayashi Y, Uchida T, Watanabe T, Oyama T, et al. (February 2011). "Phase I study of LY2469298, an Fc-engineered humanized anti-CD20 antibody, in patients with relapsed or refractory follicular lymphoma". Cancer Science. 102 (2): 432–8. doi:10.1111/j.1349-7006.2010.01809.x. PMID   21205069. S2CID   26346792.