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<p>Tumor microenvironments present significant barriers to penetration by antibodies and immunoconjugates and are difficult to study <i>in vitro</i>. Cells cultured as monolayers typically exhibit less resistance to therapy than those grown <i>in vivo. </i>Therefore, it is important to develop an alternative research model that better represents<i> in vivo</i> tumors. We have developed a protocol to produce multicellular spheroids, a simple and more relevant model of<i> in vivo </i>tumors that allows for further investigations of the microenvironmental effects on drug penetration and tumor cell killing. The protocol is used to produce<i> in vitro</i> three-dimensional tumor spheroids from established human cancer cell lines and primary cancer cells isolated from patients without the use of any extracellular components. To study the ability of tumor-targeting immunoconjugates to penetrate these tumor spheroids <i>in vitro</i>, we have used an immunotoxin targeting mesothelin, a surface protein expressed in malignant mesotheliomas. This method for producing consistent, reproducible 3D spheroids may allow for improved testing of novel monoclonal antibodies and other agents for their ability to penetrate solid tumors for cancer therapy.</p>