maytansine and Lymphoma

Antibody-drug conjugates (ADCs) combine highly specific monoclonal antibodies with potent cytotoxic drugs. Their synergy allows for targeted delivery of toxic drugs to cancer cells while sparing systemic exposure. In this review, we focus on the history and clinical applications of ADCs approved by the U.S. Food and Drug Administration (FDA) for the treatment of cancer and highlight new ADCs in the drug development pipeline. Three ADCs have received FDA approval thus far. Gemtuzumab ozogamicin, although withdrawn from the U.S. market, may still be an effective treatment modality in subsets of patients with acute myeloid leukemia. Brentuximab vedotin and ado-trastuzumab emtansine have shown improved efficacy and safety data compared with standard chemotherapy for the treatment of advanced lymphoma and breast cancer, respectively. With a number of ADCs with promising preliminary data in the clinical trial pipeline, cancer therapy is moving forward from traditional chemotherapy to targeted treatment modalities driven by the specificity of monoclonal antibodies and advancing biotechnology.

Topics: Ado-Trastuzumab Emtansine; Aminoglycosides; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Breast Neoplasms; Brentuximab Vedotin; Female; Gemtuzumab; Humans; Immunoconjugates; Leukemia, Myeloid, Acute; Lymphoma; Maytansine; Neoplasms; Trastuzumab

Topics: Animals; Chemical Phenomena; Chemistry; Digestive System; Drug Evaluation; Drug Evaluation, Preclinical; Female; Humans; Leukemia, Experimental; Leukemia, Lymphoid; Lymphoma; Maytansine; Mice; Mitosis; Neoplasms; Nervous System; Oxazines; Pregnancy; Teratogens

Antibody-drug conjugates (ADC) are a novel way to deliver potent cytotoxic compounds to cells expressing a specific antigen. Four ADC targeting CD19, including SAR3419 (coltuximab ravtansine), have entered clinical development. Here, we present huB4-DGN462, a novel ADC based on the SAR3419 anti-CD19 antibody linked

Topics: Animals; Antibodies, Monoclonal, Humanized; Antigens, CD19; Antineoplastic Agents; Cell Line, Tumor; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Humans; Immunoconjugates; Leukemia; Lymphoma; Maytansine; Mice; Treatment Outcome; Xenograft Model Antitumor Assays

Coltuximab ravtansine (SAR3419) is an antibody-drug conjugate (ADC) targeting CD19 created by conjugating a derivative of the potent microtubule-acting cytotoxic agent, maytansine, to a version of the anti-CD19 antibody, anti-B4, that was humanized as an IgG1 by variable domain resurfacing. Four different linker-maytansinoid constructs were synthesized (average ∼3.5 maytansinoids/antibody for each) to evaluate the impact of linker-payload design on the activity of the maytansinoid-ADCs targeting CD19. The ADC composed of DM4 (N(2')-deacetyl-N(2')-[4-mercapto-4-methyl-1-oxopentyl]maytansine) conjugated to antibody via the N-succinimidyl-4-(2-pyridyldithio)butyrate (SPDB) linker was selected for development as SAR3419. A molar ratio for DM4/antibody of between 3 and 5 was selected for the final design of SAR3419. Evaluation of SAR3419 in Ramos tumor xenograft models showed that the minimal effective single dose was about 50 μg/kg conjugated DM4 (∼2.5 mg/kg conjugated antibody), while twice this dose gave complete regressions in 100% of the mice. SAR3419 arrests cells in the G2/M phase of the cell cycle, ultimately leading to apoptosis after about 24 h. The results of in vitro and in vivo studies with SAR3419 made with DM4 that was [(3)H]-labeled at the C20 methoxy group of the maytansinoid suggest a mechanism of internalization and intracellular trafficking of SAR3419, ultimately to lysosomes, in which the antibody is fully degraded, releasing lysine-N(ε)-SPDB-DM4 as the initial metabolite. Subsequent intracellular reduction of the disulfide bond between linker and DM4 generates the free thiol species, which is then converted to S-methyl DM4 by cellular methyl transferase activity. We provide evidence to suggest that generation of S-methyl DM4 in tumor cells may contribute to in vivo tumor eradication via bystander killing of neighboring tumor cells. Furthermore, we show that S-methyl DM4 is converted to the sulfoxide and sulfone derivatives in the liver, suggesting that hepatic catabolism of the payload to less cytotoxic maytansinoid species contributes to the overall therapeutic window of SAR3419. This compound is currently in phase II clinical evaluation for the treatment of diffuse large B cell lymphoma.

Topics: Animals; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Cell Cycle Checkpoints; Cell Division; Cell Line, Tumor; Female; G2 Phase; Humans; Liver; Lymphoma; Maytansine; Mice; Mice, SCID; Structure-Activity Relationship; Xenograft Model Antitumor Assays

Topics: Drug Evaluation; Follow-Up Studies; Humans; Injections, Intravenous; Lymphoma; Maytansine; Oxazines