IMC-A 12 , a Human IgG 1 Monoclonal Antibody to the Insulin-Like Growth Factor IReceptor

Targeted monoclonal antibody therapy is an important strategy in cancer therapeutics. Among the most promising characteristics of therapeutic targets are those that modulate the growth and survival of malignant neoplasms and their sensitivity to anticancer therapies.The insulin-like growth factor-I receptor (IGF-IR) is overexpressed in many types of solid and hematopoietic malignancies, andhasbeen implicated as aprincipal cause of heightenedproliferative and survival signaling. IGF-IR has also been shown to confer resistance to cytotoxic, hormonal, and targeted therapies, suggesting that therapeutics targeting IGF-IRmay be effective against a broad range of malignancies. IMC-A12 (ImClone Systems Incorporated), a fully humanmonoclonal IgG1antibody that binds with high affinity to the IGF-IR, inhibits ligand-dependent receptor activation and downstream signaling. IMC-A12 also mediates robust internalization and degradation of the IGF-IR. In human tumor xenograft models, IGF-IR blockade by IMC-A12 results in rapid and profound growth inhibition of cancers of the breast, lung, colon, and pancreas, and many other neoplasms. Although promising single-agent activity has been observed, the most impressive effects of targeting the IGF-IR with IMC-A12 have been noted when this agent was combined with cytotoxic agents or other targeted therapeutics. The results with IMC-A12 to date suggest that it may be an effective therapeutic in a diverse array of oncologic indications. The insulin-like growth factor (IGF)-I receptor (IGF-IR) signaling pathway is increasingly recognized for its roles in both normal growth and development and in oncogenesis. It is a highly conserved pathway that arose, from an evolutionary standpoint, possibly to regulate cellular proliferation in response to nutrient availability. In addition to its role in modulating the balance between cellular proliferation and apoptosis, the IGF-IR and its close counterpart, the insulin receptor (IR), play key roles in regulating energy metabolism, body size, longevity, and various organ-specific functions (1–4). IGF-IR is clearly involved in normal growth and development. During puberty, serum IGF-I levels increase as pituitary-derived growth hormones induce igf-1 expression in the liver (5). Children with mutations in igf-1 and igf1r exhibit poor in utero and postnatal growth, microcephaly, and neurodevelopmental delay (6). In some animal models, disruption of IGF signaling results in reduced breast and prostate gland growth, suggesting that the IGF system modulates normal organ development (7, 8). In cancer, several model systems have provided evidence that the proliferative and metastatic potentials of cancer cells are enhanced by IGF-IR activation, either due to higher levels of circulating IGF-I or autocrine production of ligands by cancer cells (4). These critical roles of IGF-IR signaling in controlling the rates of cell renewal has led to interest in targeting the IGF-IR as a therapeutic strategy against cancer (1, 3, 5, 9). Targeting IGF-IR as aTherapeutic Strategy against Cancer The IGF-IR and its ligands IGF-I and IGF-II have been implicated as playing key roles in the development, maintenance, and progression of cancer (3, 5, 9 –15). IGF-IR activation can stimulate cellular proliferation and differentiation and protect cells from undergoing apoptosis despite robust proapoptotic stimuli. Overexpression of IGF-IR in cancer cells, often in concert with overexpression of IGF ligands, augments these signals and, as a result, enhances cell proliferation and survival. In contrast, the IGF-IIR does not transduce signals, but instead, acts as a ‘‘sink’’ for IGF-II (Fig. 1), which exerts its biological effects through the IGF-IR (3, 15). This model provides a framework to explain the observation that IGF-IIR functions like a tumor suppressor gene; loss of IGF-IIR is associated with increased IGF-II– initiated activation of IGF-IR, as well as increased proliferation. IGF-I and IGF-II are potent mitogens for a broad range of cancers in vitro including those derived from human prostate, breast, colon, ovary, and lung cancers, melanoma and multiple myeloma, and these growth-stimulatory effects are mediated Authors’Affiliations: Department of Clinical Research and Regulatory Affairs, ImClone Systems Incorporated, Branchburg, New Jersey and Department of Research, ImClone Systems Incorporated, NewYork, NewYork Received 5/8/07; accepted 5/21/07. Presented at the Eleventh Conference on Cancer Therapy with Antibodies and Immunoconjugates, Parsippany, New Jersey, USA, October12-14, 2006. Note: All authors are employees of Imclone Systems Incorporated, which is involved in developing IMC-A12, themajor therapeutic focus of themanuscript. Requests for reprints: Eric K. Rowinsky, ImClone Systems Incorporated, 33 ImClone Drive, Branchburg, NJ 08876. Phone: 908-203-6912; Fax: 908-2319885; E-mail: eric.rowinsky@imclone.com. F2007 American Association for Cancer Research. doi:10.1158/1078-0432.CCR-07-1109 www.aacrjournals.org Clin Cancer Res 2007;13(18 Suppl) September15, 2007 5549s Cancer Research. on January 22, 2018. © 2007 American Association for clincancerres.aacrjournals.org Downloaded from through the IGF-IR (3, 5, 16–25). Furthermore, high circulating levels of IGF-I have been associated with an increased risk of developing breast, prostate, and colon cancer (11). In experimental systems, the growth of many cancers that express the IGF-IR is influenced by circulating IGF-I, which is produced by tissues remote from the cancer. However, some cancers seem to be controlled, at least to some extent, by locally synthesized IGF-I and/or IGF-II, which act in an autocrine or paracrine manner. It has been proposed that cancers may be highly dependent on the host for the ligand during early stages of cancer progression, but later acquire the capacity to produce ligands in an autocrine fashion, which relate to genotypic and phenotypic changes suggestive of a more aggressive behavior. The appropriate clinical development of therapeutics targeting IGF signaling will ultimately require an understanding of the determinants of the functional importance of IGF pathways in each distinct cancer and stage, as well as the extent to which each distinct cancer depends on circulating stimulatory ligands and autocrine mechanisms. There is evidence from experimental systems and studies of clinical tumor biopsy specimens, particularly prostate cancer, which suggests that cancer progression is associated with increased expression of the IGF-IR (26, 27). However, gene amplification and protein overexpression seems to be less common for the IGF-IR than the epidermal growth factor receptor family member HER2/neu, which is commonly overexpressed in breast cancer due to gene amplification (28–30). In many cancers, IGF-IR seems to play a principal role in regulating proliferation and differentiation, even when its level of expression is low. IGF-IR signaling can also become exaggerated or aberrant due to molecular abnormalities involving downstream signaling elements. One common example is the loss of function of the tumor suppressor gene PTEN , which encodes a phosphatase that typically attenuates proliferative signals originating from the IGF-IR and other receptor tyrosine kinases (3, 29, 30). Overexpression of IGF-II in cancer cell lines and various malignant neoplasms in vivo is common and may result from loss of genomic imprinting of the IGF-II gene (31). Loss of imprinting or other regulatory failures that lead to increased IGF-II expression would be predicted to confer a growth advantage. Observations that IGF-II is the gene that is most overexpressed in colon cancer relative to normal colonic mucosa, and that loss of imprinting of IGF-II represents a risk factor for colorectal cancer, suggests an important role for IGF-II expression in cancer progression (32, 33). This is further supported by experimental evidence which suggests that the expression of IGF-II and IGF-IR is higher in highly metastatic cancers than in tumors of low metastatic potential. Fig. 1. The insulin receptor family and related ligands.The IGF-IR, which is expressed on the cell surface as a preformed dimer, shares significant homology with the insulin receptors, IR-A and IR-B, and heterodimers of IGF-IR and either IR-A or IR-B can form during protein processing inside the cell. Approximately half of the IGF-IR on the surface of the cell exists as homodimers of IGF-IR molecules, and the rest exist as heterodimers, or hybrids, of IGF-RI and IR molecules. A second IGF receptor, IGF-IIR, the mannose-6-phosphate (M6P) receptor, has high affinity for binding the IGF-II ligand, but is a nonsignaling receptor.The biological activities of the IGF ligands aremediated by IGF-IR, but the IGF-IIR is considered to function as a ‘‘sink’’ that controls the local bioavailability of IGF ligands for binding to the IGF-IR.The IGF-IIR has tumor suppressor activity and expression of this gene is lost in some tumors.The IGF ligands, IGF-I and IGF-II, bind with approximately equal affinity to the IGF-RI. However, in tumors, IGF-II predominates as the more transforming ligand.The IGFs are stabilized in the serum by a series of six IGFBPs. www.aacrjournals.org Clin Cancer Res 2007;13(18 Suppl) September15, 2007 5550s Cancer Research. on January 22, 2018. © 2007 American Association for clincancerres.aacrjournals.org Downloaded from IGF signaling through the IGF-IR has been shown to protect tumor cells from many types of insults, including damage due to cytotoxic chemotherapeutic agents, ionizing radiation, and agents targeting various steroid or peptide-hormone receptors, and effective strategies against IGF-IR may thwart these protective effects (3, 5, 18, 34). The hypothesis that targeting the IGF-IR will increase the efficacy of other anticancer therapeutics is largely based on evidence that survival signals originating at this receptor limit the e