obinutuzumab

**Class/Mechanism:** Humanized IgG1 monoclonal antibody against CD20, a transmembrane protein on pre-B and mature B cells (not on stem cells, pro-B cells, or plasma cells). It is a type II, glycoengineered (afucosylated Fc) antibody. Type II binding causes less CD20 relocalization into lipid rafts, so there is less complement-dependent cytotoxicity (CDC). It induces more direct (caspase-independent) programmed cell death. The afucosylated Fc has higher affinity for FcγRIIIa on NK cells and macrophages, which enhances antibody-dependent cellular cytotoxicity (ADCC) and phagocytosis (ADCP). In contrast, rituximab is a chimeric type I antibody with strong CDC.

**Indications:** - Previously untreated chronic lymphocytic leukemia (CLL), combined with chlorambucil. It is also used with venetoclax in a fixed-duration regimen. - Follicular lymphoma: relapsed/refractory disease after rituximab-containing therapy (with bendamustine, then as monotherapy), and untreated stage II bulky or stage III-IV disease (with chemotherapy, then as maintenance). - Lupus nephritis (adults with active class III/IV disease, added to standard therapy). B-cell depletion is the rationale. Check current labeling for any further autoimmune indications.

**Boxed warnings:** - Hepatitis B virus reactivation, which can cause fulminant hepatitis, hepatic failure, and death. Screen with HBsAg and anti-HBc before treatment. - Progressive multifocal leukoencephalopathy (PML), caused by JC virus reactivation. Think of a patient on anti-CD20 therapy with new focal neurologic deficits or cognitive decline, and demyelinating white matter lesions on MRI.

**Other adverse effects:** - Infusion-related reactions (cytokine release): fever, chills, hypotension, bronchospasm. Premedicate with a glucocorticoid, antihistamine, and acetaminophen. Reactions are often more frequent and severe with the first infusion, especially in CLL with a high circulating tumor burden. - Tumor lysis syndrome (hyperkalemia, hyperphosphatemia, hyperuricemia, hypocalcemia, AKI). Prevent with hydration and allopurinol or rasburicase. - Neutropenia (including late-onset), thrombocytopenia, infections, and hypogammaglobulinemia from prolonged B-cell depletion. - Live vaccines are contraindicated.

**High-yield comparisons:** - Rituximab: chimeric, type I, CDC-dominant. Used in B-cell NHL, CLL, RA, ITP, ANCA vasculitis, pemphigus vulgaris, and others. - Ofatumumab: fully human anti-CD20, binds a different epitope. Used in CLL and relapsing MS. - Ocrelizumab and ublituximab: anti-CD20 agents for MS. - Naming: "-mab" is a monoclonal antibody, "-zu-" is humanized, and "-tu-" is a tumor target (older nomenclature).

**Pearls:** CD20 is not expressed on plasma cells, so immunoglobulin production is partially preserved. CLL cells are CD5+, CD19+, CD20+, and CD23+. A peripheral smear shows smudge cells. Venetoclax (BCL-2 inhibitor) combined with obinutuzumab gives deep remissions but carries a significant TLS risk.