TG Therapeutics is developing ublituximab, and anti-CD20 monoclonal antibody for patients with CLL (Chronic Lymphocytic Leukemia). In a phase 3 study in patients with relapsed disease, the combination of ublituximab and ibrutinib (Imbruvica) was superior to ibrutinib, alone – the overall response rates were 80% and 47%, respectively.
Other anti-CD20 monoclonal antibodies
Rituxan (rituximab) is an anti-CD20 monoclonal antibody indicated for the treatment of Non-Hodgkin’s Lymphoma (NHL), CLL, rheumatoid arthritis, and gramulomatosis. Arzerra (ofatumumab), is an anti-CD20 monoclonal antibody indicated for the treatment of CLL. Both antibodies bind to CD20 on B-cells and trigger complement-dependent cytotoxicity (CDC) and antibody-dependent, cell-mediated cytotoxicity (ADCC). Rituxan is a first generation anti-CD20 Mab – it is chimeric (mouse/human) construct. Arzerra is a second-generation anti-CD20 Mab – it is fully human.
Ublituximab: a third-generation anti-CD20 Mab
Ublituximab is a fully human construct characterized by a specific glycosylation pattern containing a high percentage of non-fucosylated antibody molecules at the Fc site. This specific pattern of glycosylation increases the affinity of antibodies for human FcγRIIIa (CD16), resulting in an increased antibody dependent cell-mediated cytotoxicity (ADCC) by human FcγRIIIa-expressing effector cells.
FcγRIIIa, a medium affinity receptor, capable of interaction with complexed as well as monomeric IgG, is expressed on natural killer (NK) cells, macrophages, and subsets of monocytes and γδ T cells. FcγRIIIa mediates antibody-dependent cell-mediated cytotoxicity (ADCC) by NK cells and T cells, phagocytosis by macrophages, cytokine production by NK cells and lymphocytes, and regulation of immunoglobulin production.
Antibodies that have fucose-depleted Fc portions trigger more robust ADCC:
Lec13 cells, a variant Chinese hamster ovary cell line, were used to produce human IgG1 that were deficient in fucose attached to the Asn297-linked carbohydrate but were otherwise similar to that found in IgG1 produced in normal Chinese hamster ovary cell lines and from human serum. Lack of fucose on the IgG1 had no effect on binding to human FcγRI, C1q, or the neonatal Fc receptor. Although no change in affinity was found for the His131 polymorphic form of human FcγRIIA, a slight improvement in binding was evident for FcγRIIB and the Arg131 FcγRIIA polymorphic form. In contrast, binding of the fucose-deficient IgG1 to human FcγRIIIA was improved up to 50-fold. Antibody-dependent cellular cytotoxicity assays using purified peripheral blood monocytes or natural killer cells from several donors showed enhanced cytotoxicity, especially evident at lower antibody concentrations. When combined with an IgG1 Fc protein variant that exhibited enhanced antibody-dependent cellular cytotoxicity, the lack of fucose was synergistic.
The GENUINE Phase 3 Trial
One hundred-twenty-six patients who were refractory to prior therapy and had at least one high-risk cytogenetic feature defined by the presence of 17p deletion, 11q deletion and/or p53 mutation were randomized to receive ublituximab in combination with ibrutinib or ibrutinib, alone. The chromosomal aberrations are important in the DNA damage response network of the cell. 17p (the small arm of the seventeenth chromosome) is where the p53 gene is located. p53 is the guardian of the genome; deficient p53 functioning can result in runaway cell division, which is particularly concerning when significant genomic alterations are present. 11q (the long arm of the eleventh chromosome) contains the gene ATM, which is needed to pause DNA replication until chromosomal aberrations are fixed. If repair cannot be made, p53 induces apoptosis so that the clone of cells with the damaged DNA dies off. In the absence of p53 and 11q these safeguards are not in place and cancers progress more rapidly and become more aggressive because they possess highly mutable genomes.