Monoclonal Antibodies in Cancer Therapy

In our study, a novel, fully human, recombinant monoclonal antibody of the IgG1 isotype, called MT201, was characterized for its binding properties, complement-dependent (CDC) and antibody-dependent cellular cytotoxicity (ADCC), as well as for its in vivo antitumor activity in a nude mouse model. MT201 was found to bind its target, the epithelial cell adhesion molecule (Ep-CAM; also called 17-1A antigen, KSA, EGP-2, GA733-2), with low affinity in a range similar to that of the clinically validated, murine monoclonal IgG2a antibody edrecolomab (Panorexா). MT201 exhibited Ep-CAM-specific CDC with a potency similar to that of edrecolomab. However, the efficacy of ADCC of MT201, as mediated by human immune effector cells, was by 2 orders of magnitude higher than that of edrecolomab. Addition of human serum reduced the ADCC of MT201 while it essentially abolished ADCC of edrecolomab within the concentration range tested. In a nude mouse xenograft model, growth of tumors derived from the human colon carcinoma line HT-29 was significantly and comparably suppressed by MT201 and edrecolomab. The fully human nature and the improved ADCC of MT201 with human effector cells will make MT201 a promising candidate for the clinical development of a novel pan-carcinoma antibody that is superior to edrecolomab.

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

Naundorf

Preithner

Mayer

et al. 2002

Intl Journal of Cancer

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Efficient tumor cell lysis by autologous, tumor‐resident T lymphocytes in primary ovarian cancer samples by an EP‐CAM‐/CD3‐bispecific antibody

Wimberger¹,

Xiang

Mayr

et al. 2003

Intl Journal of Cancer

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The epithelial cell adhesion molecule (Ep-CAM) is expressed on the surface of most human carcinomas, including ovarian, breast, lung, prostate and colorectal carcinoma. Primary ovarian cancer is the fourth leading cause of cancer death in women. 1 Three-fourths of patients have an advanced stage referred to as FIGO III or FIGO IV at the time of diagnosis because there is a lack of an effective screening method for primary ovarian cancer at an earlier stage. Standard treatment of these patients is initial debulking surgery followed by chemotherapy. Standard chemotherapy (combination of carboplatin with paclitaxel) could not improve overall survival in a great manner. 2 The 5-year survival rate of FIGO IIIc is only 25%, and only 5% in FIGO Stage IV. Because of this prognosis, we are looking for a better causal therapy than available recently by chemotherapy.Treatment of solid tumors by recombinant monoclonal antibodies of the human IgG1 subtype has become a very promising addition to the arsenal of cancer therapeutics. IgG1 antibodies against the HER-2 (trastuzumab) 3 and EGFR antigens (C225) 4 revealed high response rates and increased time to relapse with solid tumors. The combination with chemotherapy substantially increased the efficacy of such antibodies. The anti-tumor activity of human IgG1 is based on antibody-dependent cellular cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC) and, in certain cases, on pro-apoptotic signal transduction. A recent study using knock-out mice lacking the common signaling component of Fc␥ receptors allowed to study the contribution of ADCC to the anti-tumor activity of trastuzumab. 5 In the mouse model, trastuzumab lost most of its inhibitory activity against a human tumor overexpressing HER-2, suggesting that ADCC but not pro-apoptotic signaling is a major mechanism of IgG1 action in vivo. A murine monoclonal antibody of the IgG2a subtype, called edrecolomab (Panorex ), increased overall survival in resected Dukes C colorectal cancer patients by 32%. 6

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