Reduction of Spontaneous Metastases through Induction of Carbohydrate Cross-Reactive Apoptotic Antibodies

Abstract

The selective targeting of tumor-associated carbohydrate Ags by the induction of serum Abs that trigger apoptosis of tumor cells as a means to reduce circulating tumor cells and micrometastases would be an advantage in cancer vaccine development. Some plant lectins like Griffonia simplicifolia lectin I and wheat germ agglutinin mediate the apoptosis of tumor cells. We investigated the possibility of using these lectins as templates to select peptide mimotopes of tumor-associated carbohydrate Ags as immunogens to generate cross-reactive Abs capable of mediating apoptosis of tumor cells. In this study, we show that immunization with a mimotope selected based on its reactivity with Griffonia simplicifolia lectin I and wheat germ agglutinin induced serum IgM Abs in mice that mediated the apoptosis of murine 4T1 and human MCF7 cell lines in vitro, paralleling the apoptotic activity of the lectins. Vaccine-induced anti-carbohydrate Abs reduced the outgrowth of micrometastases in the 4T1 spontaneous tumor model, significantly increasing survival time of tumor-bearing animals. This finding parallels suggestions that carbohydrate-reactive IgM with apoptotic activity may have merit in the adjuvant setting if the right carbohydrate-associated targets are identified.

Peptimmunology: Immunogenic Peptides and Sequence Redundancy

“…Peptides mimicking aa sequences present in the antigen and potentially able to induce broad responses have been identified for a number of DAPs by combinatorial peptide libraries. The "mimotope" approach was used with some success in a few animal and pre-clinical trials, but has reported autoimmune side effects too [30][31][32][33]. Likewise, fusion of peptides to lipids has resulted in conjugates of enhanced immunogenicity [34].…”

A highly bone marrow metastatic murine breast cancer model established through in vivo selection exhibits enhanced anchorage-independent growth and cell migration mediated by ICAM-1

“…The presence of anti-ICAM-1 antibody also decreased the size of the colonies of 4T1E/M3. Thus, 4T1E/M3 cells 1-4), HindIII (lanes 5-8), EcoO109I (lanes 9-12) or BamHI (lanes [13][14][15][16] and then separated by electrophoresis on 0.8% agarose gel, transferred to nylon membrane, and hybridized with 32 P-labeled neo-gene probe and visualized by image analyzer Fig. 4 In vitro proliferation activity of parent or 4T1E/M3 cells.…”

“…BALB/c-derived 4T1 spontaneous mouse mammary carcinoma cell line [12] was shown to closely mimic human breast cancer with respect to its immunogenicity, metastatic properties and growth characteristics [13,14]. These cells have been used to develop a number of immunotherapies [15][16][17]. We, therefore, decided to use 4T1 cells to establish its bone marrow metastatic variant.…”

Carbohydrate Mimotopes in the Rational Design of Cancer Vaccines

“…Such results suggest that TACA-targeting vaccines might have a beneficial effect on the course of malignant disease. Preclinical studies support the hypothesis that vaccine-induced responses against TACA might have their greatest impact in the adjuvant setting as such responses inhibit tumor outgrowth in metastatic models [29,30]. On human tumor cells, antibodies that recognize glycolipids are more apt to mediate complement-dependent cytotoxicity (CDC) and may, therefore, be more cytotoxic to tumor cells than antibodies that recognize protein antigens [31].…”