Lorvotuzumab mertansine, a CD56-targeting antibody-drug conjugate with potent antitumor activity against small cell lung cancer in human xenograft models.
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.
ImmunoGen, Inc; Waltham, MA USA.
Kathleen R
KR
Whiteman
ImmunoGen, Inc; Waltham, MA USA.
Holly A
HA
Johnson
ImmunoGen, Inc; Waltham, MA USA.
Michele F
MF
Mayo
ImmunoGen, Inc; Waltham, MA USA.
Charlene A
CA
Audette
ImmunoGen, Inc; Waltham, MA USA.
Christina N
CN
Carrigan
ImmunoGen, Inc; Waltham, MA USA.
Alyssa
A
LaBelle
Harvard Medical School and Massachusetts General Hospital; Boston, MA USA.
Lawrence
L
Zukerberg
ImmunoGen, Inc; Waltham, MA USA.
John M
JM
Lambert
ImmunoGen, Inc; Waltham, MA USA.
Robert J
RJ
Lutz
D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry / Q000276:immunology / Q000378:metabolism*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D019002:CD56 Antigen / Q000276:immunology*; D045744:Cell Line, Tumor; D003602:Cytotoxicity, Immunologic; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D008175:Lung Neoplasms / Q000276:immunology / Q000628:therapy*; D008453:Maytansine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D016513:Mice, SCID; D055752:Small Cell Lung Carcinoma / Q000276:immunology / Q000628:therapy*; D050257:Tubulin Modulators / Q000737:chemistry / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
D000911:Antibodies, Monoclonal; D019002:CD56 Antigen; D050257:Tubulin Modulators; C579429:lorvotuzumab mertansine; D008453:Maytansine
ADC; CD56; antibody-drug conjugate; combination therapy; maytansinoid; small cell lung cancer; xenografts