loncastuximab tesirine-lpyl — Drug Monograph

Brand names: Zynlonta

Drug class: Antibody-Drug Conjugate

Mechanism of Action

Anti-CD19 monoclonal antibody conjugated to SG3199, a highly potent pyrrolobenzodiazepine (PBD) dimer, via a protease-cleavable linker. After internalization, SG3199 cross-links DNA in the minor groove, causing irreversible DNA double-strand breaks and cell death. The PBD dimer payload is significantly more potent than MMAE, enabling activity at ultra-low payloads.

FDA Indications

• Relapsed or refractory large B-cell lymphoma (LBCL) after ≥2 prior lines of systemic therapy, including diffuse large B-cell lymphoma (DLBCL) NOS, DLBCL arising from low-grade lymphoma, and high-grade B-cell lymphoma (accelerated approval April 2021; LOTIS-2: ORR 48.3%, CR 24.1%)

Common Side Effects

• Pleural effusion
• Peripheral edema / generalized edema
• Fatigue
• Nausea
• Neutropenia
• Thrombocytopenia
• GGT elevation (gamma-glutamyltransferase)
• Anemia
• Hyperglycemia (from corticosteroid prophylaxis)

Clinical Pearl

Loncastuximab-tesirine carries a notably different toxicity profile from MMAE-based ADCs: the dominant issues are effusions and edema (PBD dimer class effects) rather than neuropathy. The mandatory dexamethasone 4 mg BID × 3-day prophylaxis per cycle is essential to prevent life-threatening fluid accumulation. GGT elevation is very common (~80%) and largely asymptomatic; it does not always require dose modification and should be distinguished from hepatocellular injury.

Related Therapies & Mechanisms

• Brentuximab Vedotin (Adcetris) — Antibody-Drug Conjugate · Lymphoma
• Polatuzumab vedotin (Polivy) — Antibody-Drug Conjugate · Lymphoma
• Belantamab mafodotin (Blenrep) — Antibody-Drug Conjugate
• Datopotamab deruxtecan-dlnk (Datroway) — Antibody-Drug Conjugate