Monoclonal antibody KS1/4-methotrexate immunoconjugate studies in non-small cell lung carcinoma.

Abstract

The antigen reactive with murine monoclonal antibody (MAb) KS1/4 is expressed on epithelial malignancies and some normal epithelial tissues. Studies were undertaken to evaluate KS1/4-methotrexate (KS1/4-MTX) immunoconjugate in patients with advanced non-small cell carcinoma of the lung. Eleven patients in two different groups received KS1/4-MTX in two different escalating dose infusion schedules with a maximal tolerated dose of 1,750 mg/M2 and a cumulative dose of MTX of 40 mg/M2. Toxicities were similar in both groups and included fever, anorexia, nausea, vomiting, diarrhea, abdominal pain, guaiac positive stool, and hypoalbuminemia. Two patients had an associated aseptic meningitis. One patient had a 50% decrease in two lung nodules without a change in lymphangitic infiltrates. This patient received a second course of treatment and developed an immune complex-mediated arthritis and serum sickness. Four patients mounted a human antimouse antibody response. Post-treatment tumor biopsies documented binding of MAb KS1/4. These studies document the feasibility and potential usefulness of a MAb directed against tumor-associated antigens with the targeting of chemotherapeutic drugs in patients with non-small cell lung carcinoma.

Antibody Drug Conjugates for Cancer Therapy

“…Some of the earlier iterations of ADCs tested in the clinic included the incorporation of antimitotics and antimetabolites approved for use in chemotherapy as unconjugated cytotoxins (Ford et al, 1983;Oldham et al, 1988;Elias et al, 1990;Petersen et al, 1991;Krauer et al, 1992;Takahashi et al, 1993). These early clinical ADCs suffered from a panoply of issues, not the least of which was a drug likely too impotent for targeted delivery.…”

Epithelial Cell Adhesion Molecule (KSA) Expression

“…Given its plasma membrane distribution, significant attention has also been directed to the molecule as a target for immunotherapy using either unconjugated (31)(32)(33)(34)(35) or conjugated (36) anti-EpCAM antibodies of varying affinity. Five and 7-year mortality rates were reduced for patients with minimal residual colorectal cancer using the low-affinity anti-EpCAM antibody edrecolomab (Panorex), which has been approved for clinical use in Germany (34,37).…”

In vitro and in vivo activity of MT201, a fully human monoclonal antibody for pancarcinoma treatment

“…20 -22 Conjugates of other Ep-CAM antibodies with toxins also showed significant side effects as is expected for antibodies attacking epithelia. 23 Edrecolomab and 3622W94 were reported to bind the same subdomain of Ep-CAM, 24 suggesting that affinity and not epitope recognition was responsible for the difference in tolerability. A drawback of edrecolomab for human therapy is its murine nature, resulting in a neutralizing immune response, short serum half-life, no option for chronic treatment and reduced compatibility with human immune effector mechanisms.…”