Note: Blue indicates commercial products/application; yellow indicates potential products/applications		Rituxan® Rituximab (a) Genentech	Herceptin® Trastuzumab (b) Genentech	Erbitux® Cetuximab (c) Imclone & Bristol Myers Squibb	Avastin® Bevacizumab (d) Genentech	Sphingomab™ Anti-S1P mAb Lpath
Inhibition of metastatis		Binds CD20 protein	Binds HER2 receptor	Binds HER1 receptor	Molecular sponge for VEGF	Molecular sponge for S1P
Approved for which cancers		Non-Hodgkin's lymphoma (NHL)	Metastatic breast cancer	Metastatic colorectal cancer	Metastatic colorectal cancer	n.a.
In clinical trials for which cancers		n.a.	n.a.	n.a.	Renal cell (kidney), breast and non-small cell lung cancers	Efficacy demonstrated in pre-clinical studies against the following: ovarian, lung, and breast cancer; melanoma; multiple myeloma; lymphoma
Other disease indications:		n.a.	n.a.	n.a.	Lucentis™, a fab fragment of Avastin®, is in clinical trials for Age-related Macular Degeneration (AMD)	AMD, cardiovascular diseases, AMD, inflammatory diseases
Direct effect on Angiogenesis
Direct effects on tumor cells themselves	Inhibition of metastasis
	Tumor cell growth
	Tumor cell death

Footnotes
(a) Rituxan® recognizes the CD20 protein expressed on the surface of malignant B cells in the low grade or follicular non-Hodgkin's lymphoma (NHL). The marked B-cells are then attacked and killed by the body's natural defenses. The direct effects of Rituxan include complement-mediated cytotoxicity and antibody-dependent cell-mediated cytotoxicity. The indirect effects include structural changes, apoptosis, and sensitization of cancer cells to chemotherapy (Cerny, Borisch et al. 2002). Rituxin® is a registered trademark of Biogen Idec Inc.

(b) Herceptin® is a recombinant humanized monoclonal antibody specific for the external domain of ErbB2 (Cobleigh, Langmuir et al. 2003). The ErbB2 family of protein tyrosine kinases includes the human epidermal growth factor receptors (HER 1-4) and is overexpressed in many solid tumors. Herceptin is now widely used as single agent or in combination therapy for the HER-2/new (human epidermal growth factor receptor 2) overexpressing metastatic breast cancers. Herceptin interferes with the HER-2/new signaling pathways. As a direct consequence, Herceptin blocks tumor cell proliferation and induces cell damage and death both in vitro and in vivo models. Furthermore Herceptin inhibits tumor angiogenesis, induces tumor normalization and modulating different pro (reduces VEGF in vitro but not in vivo, TGF-1, PAI-1 and Ang-1 expression) and anti (increase of TSP-1 expression) angiogenic factors (Izumi, Xu et al. 2002). Herceptin also manifests immunomodulatory activity (Emens 2005). Herceptin binds only one, the HEF-2/new, to the four HEF receptors identified until now. Herceptin® is a registered trademark of Genentech Inc.

(c) Erbitux® is a chimeric human-murine monoclonal antibody against EGFR (HEF-1). Binding to EGFR, Erbitux prevents the receptor stimulation by the endogenous ligands. In this way, Erbitux inhibits tumor cell proliferation, enhances apoptosis, and reduces angiogenesis (inducing downregulation of VEGF (Petit, Rak et al. 1997), invasiveness and metastasis (Bryant, Finn et al. 2004). As a consequence of the complex formation between EGFR and Erbitux, the antibody is also responsible for receptor internalization and the downregulation. Erbitux binds only one, the HEF-1 or EGFR, to the four HEF receptors identified. Erbitux® is a registered trademark of Imclone Systems Incorporated.

(d) Avastin® is a humanized mAb against the pro-angiogenic growth factor, VEFG. VEGR2 and VEGFR1 have been recently identified on some tumor cell lines including non small cell lung carcinomas (NSCL), breast cancer (T-47D), neuroblastoma (SK-N-LO, SK-N-SH, LS, SH-SY5Y, IMR-32, Kelly), Kaposi carcinoma, leukemia (IMC-1C11) and gastric cancer (MGC803). Although the main effect of VEGF is on angiogenesis, the unexpected presence of VEGF receptors on the tumor cell surface has suggested that VEGF may act also as an autocrine factor to induce tumor cell proliferation, protection from apoptosis and cell migration. However, the EMEA scientific discussion (2005) reported that the murine form of Avastin, mAb A4.6.1, tested using the rhabdomyosarcoma (A675), glioblastoma (G55) and the leiomyosarcoma (SK-LMS-1) cell lines showed no effects on tumor growth in vitro models (Kim, Li et al. 1993). On the contrary, when the cell lines were inoculated into nude mice, animals in treatment with mAb A4.6.1 presented a significant reduction in tumor growth as a direct consequence on the suppression of tumor vascularization. In other animal models using a colon carcinoma, a prostate cancer and Wilm's tumor, the treatment with A4.6.1 not only inhibited the primary tumor growth but also reduced metastasis to liver and lung. In these preclinical models, the therapeutic effects of the mAb A4.6.1 have been attributed to a direct effect on tumor angiogenesis rather than on tumor cells. Avastin recognizes all the VEGF-A isoforms (165, 121) but not VEGF-B and VEGF-C. Avastin® is a registered trademark of Genentech Inc.

Note: Avastin® is a registered trademark of Genentech, Inc.