Lorvotuzumab mertansine, a CD56-targeting antibody-drug conjugate with potent antitumor activity against small cell lung cancer in human xenograft models

• Published in: mAbs Vol. 6; no. 2; pp. 556 - 566
• Main Authors: Whiteman, Kathleen R, Johnson, Holly A, Mayo, Michele F, Audette, Charlene A, Carrigan, Christina N, LaBelle, Alyssa, Zukerberg, Lawrence, Lambert, John M, Lutz, Robert J
• Format: Journal Article
• Language: English
• Published: United States Taylor & Francis 01-03-2014; Landes Bioscience
• Subjects: ADC; Animals; Antibodies, Monoclonal - chemistry; Antibodies, Monoclonal - immunology; Antibodies, Monoclonal - metabolism; antibody-drug conjugate; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; CD56; CD56 Antigen - immunology; Cell Line, Tumor; combination therapy; Cytotoxicity, Immunologic; Drug Synergism; Drug Therapy, Combination; Female; Humans; Immunotherapy - methods; Lung Neoplasms - immunology; Lung Neoplasms - therapy; Maytansine - analogs & derivatives; Maytansine - chemistry; Maytansine - immunology; Maytansine - metabolism; maytansinoid; Mice; Mice, SCID; small cell lung cancer; Small Cell Lung Carcinoma - immunology; Small Cell Lung Carcinoma - therapy; Tubulin Modulators - chemistry; Tubulin Modulators - metabolism; Xenograft Model Antitumor Assays; xenografts; ADC; maytansinoid; antibody-drug conjugate; xenografts; combination therapy; small cell lung cancer; CD56
• ISSN: 1942-0862; 1942-0870; 1942-0870; 1942-0862
• DOI: 10.4161/mabs.27756

Lorvotuzumab mertansine (LM) is an antibody-drug conjugate composed of a humanized anti-CD56 antibody, lorvotuzumab, linked via a cleavable disulfide linker to the tubulin-binding maytansinoid DM1. CD56 is expressed on most small cell lung cancers (SCLC), providing a promising therapeutic target for treatment of this aggressive cancer, which has a poor five-year survival rate of only 5-10%. We performed immunohistochemical staining on SCLC tumor microarrays, which confirmed that CD56 is expressed at high levels on most (~74%) SCLC tumors. Conjugation of lorvotuzumab with DM1 did not alter its specific binding to cells and LM demonstrated potent target-dependent cytotoxicity against CD56-positive SCLC cells in vitro. The anti-tumor activity of LM was evaluated against SCLC xenograft models in mice, both as monotherapy and in combination with platinum/etoposide and paclitaxel/carboplatin. Dose-dependent and antigen-specific anti-tumor activity of LM monotherapy was demonstrated at doses as low as 3 mg/kg. LM was highly active in combination with standard-of-care platinum/etoposide therapies, even in relatively resistant xenograft models. LM demonstrated outstanding anti-tumor activity in combination with carboplatin/etoposide, with superior activity over chemotherapy alone when LM was used in combinations at significantly reduced doses (6-fold below the minimally efficacious dose for LM monotherapy). The combination of LM with carboplatin/paclitaxel was also highly active. This study provides the rationale for clinical evaluation of LM as a promising novel targeted therapy for SCLC, both as monotherapy and in combination with chemotherapy.