Clinical Cancer Research 13, 5549s, September 15, 2007. doi: 10.1158/1078-0432.CCR-07-1109
© 2007 American Association for Cancer Research
Cancer Therapy with Antibodies and Immunoconjugates |
IMC-A12, a Human IgG1 Monoclonal Antibody to the Insulin-Like Growth Factor I Receptor
Eric K. Rowinsky1,
Hagop Youssoufian1,
James R. Tonra2,
Phillip Solomon2,
Douglas Burtrum2 and
Dale L. Ludwig2
Authors' Affiliations: 1 Department of Clinical Research and Regulatory Affairs, ImClone Systems Incorporated, Branchburg, New Jersey and 2 Department of Research, ImClone Systems Incorporated, New York, New York
Requests for reprints: Eric K. Rowinsky, ImClone Systems Incorporated, 33 ImClone Drive, Branchburg, NJ 08876. Phone: 908-203-6912; Fax: 908-231-9885; E-mail: eric.rowinsky{at}imclone.com.
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Abstract
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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, and has been implicated as a principal cause of heightened proliferative and survival signaling. IGF-IR has also been shown to confer resistance to cytotoxic, hormonal, and targeted therapies, suggesting that therapeutics targeting IGF-IR may be effective against a broad range of malignancies. IMC-A12 (ImClone Systems Incorporated), a fully human monoclonal IgG1 antibody 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).
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Targeting IGF-IR as a Therapeutic Strategy against Cancer
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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.
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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 are mediated 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.
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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 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.
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 efficacy of agents that may otherwise induce apoptosis. For many cancers, in vitro dose-response curves of apoptosis-inducing cytotoxic agents can be shifted by varying the concentration of IGF-I in the experimental system. Indeed, recent evidence suggests that resistance to the anti-HER2 antibody trastuzumab (Herceptin; Genentech) in some forms of breast cancer is due to the activation of IGF-IR signaling and that IGF-IR blockade can restore sensitivity (34). This evidence, together with other examples, such as synergistic induction of apoptosis when small cell lung cancer is targeted by both c-KIT and IGF-IR inhibitors, suggests that IGF-IR blockade sensitizes certain cancers to other kinase inhibitors (35). Consequently, inhibition of IGF-IR signaling has been shown to increase the susceptibility of tumor cells to chemotherapeutic agents and ionizing radiation, suggesting that it is a logical target for therapeutic intervention (36). Furthermore, IGF signaling can induce the secretion of vascular endothelial growth factor (VEGF), which is central to the promotion of dysregulated malignant angiogenesis, implying the presence of an angiogenic component to the biological activity of the IGF-IR signaling cascade (37, 38). It would therefore follow that strategies to inhibit IGF-IR would suppress VEGF secretion, potentially slowing vascular expansion in treated tumors. Indeed, anti–IGF-IR therapy may enhance the activity of anti-VEGF treatment by potentially suppressing the secretion of tumor-associated VEGF.
Several therapeutic strategies, including the use of murine monoclonal antibodies directed against the human IGF-IR, have been shown to inhibit the proliferation of a broad range of cancers both in vitro and in vivo (3, 5, 39–42). These studies have established that targeting the IGF-IR is an effective means to inhibit IGF-IR signaling and is an attractive therapeutic strategy against cancer. In response, considerable interest has arisen in the biopharmaceutical industry to develop effective targeted agents to the IGF-IR signaling pathway. Central to this approach has been the development of monoclonal antibodies against the IGF-IR and its ligands. Antibody strategies targeting the extracellular domain of the IGF-IR may be advantageous compared with small molecule kinase inhibitors by being highly selective against the IGF-IR, given its close homology to the IR kinase domain.
The fully human IgG1 monoclonal antibody IMC-A12 (ImClone Systems Incorporated) was engineered to selectively bind to the IGF-IR, thereby antagonizing ligand binding and signaling through downstream mitogen-activated protein kinase and phosphoinositide-3-kinase/AKT pathways (43). IMC-A12 was developed by screening a human Fab phage display library to specifically yield a high-affinity monoclonal antibody (4.11 x 10–11 mol/L; IC50, 0.6-1 nmol/L). Considerable preclinical evidence suggests that IMC-A12 as a single agent may be effective against many types of cancer, but the therapeutic benefits of IMC-A12 seem to be enhanced greatly when it is combined with various types of nonspecific cytotoxic and targeted therapeutics. IMC-A12 was specifically engineered as an IgG1 monoclonal antibody to engage immune effector functions such as antibody-dependent cellular cytotoxicity and complement-mediated cell cytotoxicity as additional anticancer mechanisms; however, the contribution of immune effector functions in conferring the anticancer effects of IMC-A12 have not been fully evaluated.
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Single-Agent Activity of IMC-A12 against Solid Cancers
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Screening studies of human tumor biopsies for IGF-IR expression have shown that IGF-IR is expressed and up-regulated in most types of human cancer (44). However, gene amplification or activating mutations do not account for these phenomena. Instead, the predominant mechanism for overexpression is up-regulation, which is due, in part, to negative regulation by tumor suppressor proteins such as p53 and WT1 (45, 46). As a result, the concentration of IGF-IR on tumor cells is typically on the order of 50,000 to 100,000 receptors per cell, and not in the millions of copies per cell, which is commonly observed for HER family members like HER2/neu (35). Indeed, Rubini et al. have shown that a transition from 15,000 to 22,000 receptors per cell can modify the mitogenic response of cells to IGF-I and enhance cellular transformation (35). In this regard, it is important to note that, in addition to directly blocking ligand binding to the IGF-IR, IMC-A12 induces rapid receptor internalization and degradation (43). Thus, IMC-A12 treatment may reduce the levels of IGF-IR on tumor cells to below the threshold required for tumor promotion and/or resistance to anticancer therapeutics.
IMC-A12 has shown notable activity against a wide range of human tumor types in vitro, as well as in both xenograft and orthotopic models. The effects of IMC-A12 treatment were initially evaluated in a series of studies involving human MCF7 breast, BxPC-3 pancreas, and Colo205 colon carcinomas, all of which express IGF-IR and are responsive to IGF-I ligand stimulation (43). Treatment of MCF7 breast tumors with IMC-A12 as a single agent at doses of 0.01, 0.1, and 1 mg (
0.4-40 mg/kg) every 3 days significantly inhibited tumor growth in animals treated with the two highest doses, but the lowest dose produced negligible activity. Immunohistochemical studies showed a 20% reduction in proliferating cells in tumors procured from mice treated with IMC-A12. A 6-fold increase in apoptotic cells was also observed. In fact, the ratio of apoptotic to proliferating cells in tumors treated with IMC-A12 was nearly 10-fold greater than in untreated tumors. Because treatment of animals bearing MCF7 tumors with 1 mg of IMC-A12 completely inhibited tumor growth, this dose was used in subsequent studies involving BxPC-3 and Colo205. Indeed, IMC-A12 treatment imparted significant antitumor activity in the Colo205 xenografts, effecting >70% tumor growth inhibition. Similarly, IMC-A12 treatment inhibited the growth of BxPC-3 xenografts by 80%. As shown in mitogenic assays, BxPC-3 tumors were quite responsive to IGF-I stimulation in vitro and IMC-A12 treatment markedly inhibited tumor growth in vivo. Pharmacokinetic analyses suggest that a circulating threshold level of IMC-A12 in the range of 60 to 80 µg/mL is sufficient to produce maximal antitumor activity in this model. Furthermore, IMC-A12, which is a phage-selected antibody and readily cross-reacts with the mouse IGF-IR, has not been associated with notable toxicity in IMC-A12–treated rodents and primates. Since these early experiments, IMC-A12 has also shown potent activity as a single agent against other xenograft models of human breast, colon, and pancreatic cancers, as well as human non–small cell and small cell lung, prostate, renal, thyroid, and head and neck carcinoma, and multiple myeloma, sarcoma, and other cancers (47–52).3
Due to cumulative experimental evidence suggesting that IGF-IR and its ligands play key roles in the development, maintenance, and natural history of advanced prostate cancer, Wu et al. studied the effects of IMC-A12 in several human prostate cancer xenografts including both androgen-dependent (AD) and androgen-independent (AI) variants (52). IMC-A12 treatment prominently reduced the growth rates of both AD and AI variants, suggesting that IGF-IR contributes to tumor progression not only in AD prostate cancer, but also in more aggressive AI variants. Furthermore, IMC-A12 treatment induced both G1 arrest and apoptosis in the AD tumors, whereas G2-M arrest was the predominant cell cycle effect in AI tumors. These observations suggest that IGF-IR plays distinct roles in the growth and maintenance of AD and AI prostate cancers. Interestingly, blocking IGF-IR signaling and expression after castration in an AD prostate cancer model following treatment with IMC-A12 results in significantly greater antiproliferative effects compared with castration alone, and both measures significantly prolong the time to the development of AI disease (53). In addition to prolonging the development of AI in prostate cancer models, there is preliminary evidence that hormone-sensitive breast cancers retain activity to IMC-A12 following the development of tamoxifen resistance, and that IGF-IR modulation is associated with the development of resistance to hormonal therapy (54).
Similar to the experience with therapeutics targeting the epidermal growth factor receptor, the magnitude of IGF-IR expression does not seem to be a principal determinant of response to IMC-A12 in preclinical studies. Additionally, due to the high degree of homology between the IGF-IR and the IR, heterodimerization between the IR and IGF-IR typically occur in cells expressing IGF-IR (55). These hybrid receptors preferentially bind IGFs, and therefore, may behave similar to that of IGF-IR homodimers. However, the results of immunoprecipitation studies have suggested that IMC-A12 can bind, and therefore block, hybrid receptors in tumor cells.3 Adding to the complexity of the IGF-IR/IR receptor family, a fetal form of the insulin receptor, IR-A, an alternatively spliced isoform of IR, has been recently shown to be a high-affinity receptor for IGF-II and may constitute an alternative IGF-signaling mechanism that could escape targeting by IGF-IR–selective agents (56). However, the expression level of IR-A does not seem to relate with the response to IMC-A12 treatment.3
In most experimental tumors evaluated to date, single-agent IMC-A12 treatment inhibits, but typically does not fully arrest tumor growth. Indeed, there are models, such as the human pancreatic BxPC3 and MIA-Pa-Ca-2 cancers, which respond robustly to IMC-A12, suggesting that therapeutics targeting IGF-IR may produce profound effects in settings in which the IGF-IR pathway plays a dominant role in promoting tumor growth. Nevertheless, the cumulative results of preclinical studies suggest that, although a subset of tumors is likely to respond robustly to therapies targeting IGF-IR, the most profound effects occur when IGF-IR–targeted therapeutics are combined with conventional cytotoxics and/or other types of therapeutic agents.
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IMC-A12 Enhances the Activity of Cytotoxic Therapeutics
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IGF-IR overexpression has been consistently shown to protect malignant cells from the damage caused by many types of cytotoxic chemotherapeutics. Therefore, IGF-IR signaling may confer resistance to these agents (18). There is also a wide body of preclinical evidence which suggests that activation of survival pathways, particularly the phosphoinositide-3-kinase/AKT pathway, in response to cytotoxic insults, is perhaps one of the most important mechanisms of resistance to cytotoxic agents (57). Activation of the p38 pathway via IGF-IR signaling is another relevant mechanism that confers cancer cell resistance to the lethal effects of DNA-damaging agents, possibly by augmenting DNA repair mechanisms (58). Trojanek et al. have provided further evidence for a principal role of IGF-IR signaling in the DNA repair response to damage by showing a direct interaction between IRS-1 and the DNA repair protein Rad51, which is regulated by signaling through the IGF-IR (59). Phosphorylation of IRS-1 via IGF-IR releases the complex, enabling nuclear translocation of Rad51 to sites of DNA damage. Furthermore, inhibition of IGF-IR signaling seems to increase the sensitivity of tumor cells to cytotoxic therapy (36, 58, 60).
Favorable cytotoxic interactions have been noted between inhibitors of IGF-IR and most classes of nonspecific chemotherapeutic agents (alkylating agents, platinating agents, Vinca alkaloids, taxanes, antimetabolites, and inhibitors of topoisomase I and II) in vitro and in both xenograft and orthotopic models of both solid and hematopoietic cancers implanted into mice. Additive and/or synergistic interactions between IMC-A12 and almost every class of cytotoxic agents, particularly agents that affect and/or damage DNA, have been a consistent theme of preclinical evaluations.3
One recent example is provided in a study by Wu et al., who evaluated the effects of IMC-A12 treatment in preclinical models of multiple myeloma (61). Although most of the myeloma cell lines evaluated were shown to express IGF-IR, and the xenograft models derived from these lines were modestly to significantly inhibited by IMC-A12 treatment, IMC-A12 combined with either melphalan or bortezomib had much greater effects on diminishing tumor burden and prolonging survival than either melphalan or bortezomib alone. In a disseminated xenograft model, the effects of treatment on tumor burden, as determined by luciferase bioimaging, and prolongation of overall survival, were significantly greater when the therapies were combined. In addition, IMC-A12–treated tumors had significantly decreased vascularization compared with control tumors. Inhibition of IGF-IR by IMC-A12 in vitro suppressed both constitutive and IGF-I–induced abundant secretion of VEGF, indicating that a putative antiangiogenic mechanism associated with the IMC-A12 treatment may contribute to its antitumor effect. In a similar fashion, Wang et al. evaluated the activity of IMC-A12 in animal models of anaplastic thyroid cancer, which constitutes 2% of all cases of thyroid cancer, but yet is responsible for 30% of all thyroid cancer deaths (50). In contrast to previous investigations that used subcutaneous xenograft models, orthotopic cancer models were used. Single-agent treatment with irinotecan, which possesses modest activity in patients with thyroid cancer, plus IMC-A12, resulted in 57% and 80% decrements in tumor volume, respectively, whereas tumor volume was reduced by 93% following treatment with the combination of irinotecan and IMC-A12. In addition, a substantial survival advantage was observed with the combined treatment.
Wu et al. expanded on their preclinical studies of IMC-A12 in prostate cancer to explore the effects of targeting IGF-IR in combination with docetaxel, which is indicated for the treatment of advanced metastatic AI prostate cancer (52). Treatment of a LuCaP35v AI prostate cancer xenograft, with IMC-A12 plus docetaxel resulted in anticancer activity that greatly exceeded that observed with docetaxel alone. Furthermore, complete and protracted tumor growth arrest and, in some cases, tumor regression, which was not noted with docetaxel alone, were observed with the combined regimen. Additionally, once drug treatment had ceased, the tumors treated with docetaxel resumed growth, whereas tumors treated with the combination remained either static or continued to regress. However, IMC-A12 was detected in the blood up to 3 weeks following antibody treatment, suggesting that the durable antitumor effects may have been due, at least in part, to the protracted systemic availability of IMC-A12. Combined treatment with IMC-A12 and docetaxel resulted in a dramatic increase in apoptosis concomitant with a marked reduction in the proliferation cellular fraction compared with docetaxel alone. These results were further supported by differential gene expression analysis of treated tumors, which showed a marked change in the expression of genes involved in controlling apoptosis and cell cycle progression such as survivin and cyclin-dependent kinase-2. Because prostate cancer commonly metastasizes following the development of AI, the investigators further sought to evaluate the effects of combined treatment with IMC-A12 and docetaxel on established osteoblastic bone metastases of prostate cancer. Although treatment with either docetaxel alone or the combination of docetaxel plus IMC-A12 was effective in controlling the progression of osseous metastases, the antitumor effects of the combined regimen persisted long after cessation of treatment. These results provide further evidence that inhibition of IGF-IR–responsive prosurvival or repair mechanisms with targeted therapy can dramatically increase the antitumor response of AI prostate cancer to cytotoxic therapy.
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Prospects for Combinations with Targeted Therapies
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The results of preclinical studies to date support the concept of evaluating therapeutics targeting IGF-IR combined with agents that specifically thwart other signal transduction pathways. For example, impressive antitumor activity following treatment of a variety of well-established human tumor xenografts, including those derived from pancreatic and colorectal tissues, with IMC-A12 combined with the anti–epidermal growth factor receptor antibody cetuximab have been noted (62, 63). In these studies, profound tumor growth inhibition and overt tumor regression were observed at subtherapeutic single agent doses of both cetuximab and IMC-A12. Goetsch et al. have reported similar results, manifested by impressive inhibition of tumor growth, following treatment of human MCF7 breast and A549 non–small lung cancer xenografts with cetuximab plus h7C10, a human anti–IGF-IR antibody, or its murine parental 7C10 form (64). In addition, combined treatment with antibodies to the epidermal growth factor receptor and IGF-IR significantly prolonged the life span of mice in an orthotopic model of A549 non–small cell lung cancer (64). In studies involving both orthotopic and xenograft models of human breast and lung cancers, combined treatment with antibodies targeting IGF-IR and epidermal growth factor receptor were superior to the anti–IGF-IR antibody combined with chemotherapy (vinorelbine; ref. 64). Interestingly, triple-targeted antibody therapy using IMC-A12, cetuximab, and DC-101, a monoclonal antibody to the VEGF receptor-2, showed profound antitumor activity in 11 human tumor xenograft models, including colorectal, pancreas, and head and neck cancers, that could not be achieved by treatment with high-dose monotherapy (65). Because tumor cells commonly overexpress or up-regulate multiple growth factor signaling pathways, the presence of more than one growth factor would be expected to potentiate growth. Therefore, it is not unanticipated that the combination of multiple targeted therapies would be significantly more active than each individual therapeutic alone. Furthermore, in the case of IGF-targeting agents, because there is likely an antiangiogenic component to the inhibition of this pathway, combining anti–IGF-IR and anti–VEGF receptor-2 therapies would be expected to have at least additive benefit over single-agent treatment.
IGF-IR and downstream signaling has been shown to be activated in trastuzimab-resistant HER2 breast cancer, as previously discussed, and experimental results suggest that IGF-IR blockade can restore trastuzimab sensitivity (34). In fact, there is experimental evidence which suggests that trastuzimab-resistant breast cancer is particularly sensitive to IMC-A12 (54). These observations, together with other examples, such as synergistic induction of apoptosis when small cell lung cancer is targeted by both c-KIT and IGF-IR inhibitors, suggest that IGF-IR blockade might enhance tumor sensitivity to other kinase inhibitors (66).
More recently, favorable interactions between inhibitors of IGF-IR and therapeutics targeting Raf/MEK/ERK and phosphoinositide-3-kinase/AKT/mTOR pathways have also been described. In an experiment involving the hematopoietic cell line FDC-P1, which had been rendered interleukin-3–independent in a ligand-dependent manner through retroviral-mediated expression of IGF-IR (FD/IGF-IR), IMC-A12 treatment arrested IGF-I and insulin-induced FD/IGF-IR cell proliferation in G1 phase, and induced a profound degree of apoptosis (67). The effectiveness of IMC-A12 could also be enhanced by combining it with small molecule inhibitors of the mitogen-activated protein kinase and phosphoinositide-3-kinase/AKT/mTOR pathways. For example, O'Reilly et al. have shown impressive interactions between inhibitors of mTOR (rapamycin analogues) and IGF-IR, which may explain the modest clinical antitumor effects noted with mTOR inhibitors administered alone, even in tumors that possess mutational activation of the phosphoinositide-3-kinase/AKT pathway (29). The investigators showed that mTOR inhibitors induce IGF-IR expression and activation, and abrogate feedback inhibition of the pathway, which, in turn, activates AKT. Moreover, IGF-IR targeting with either IMC-A12 or small molecules prevent rapamycin-induced AKT activation and sensitizes tumor cells to mTOR inhibitors. In contrast, IGF-I reversed the antiproliferative effects of mTOR inhibitors. These results suggest that feedback down-regulation of receptor tyrosine kinase signaling is common in tumors with constitutive mTOR activation. Additionally, combined treatment with inhibitors of mTOR and IGF-IR produced much greater antitumor activity than single-agent treatment with inhibitors of mTOR or IGF-IR. Interestingly, abrogation of PTEN does not confer resistance to the anti–IGF-IR monoclonal antibody IMC-A12 in IGF-I–responsive tumor cells (68).
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Early Clinical Development of IMC-A12
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The design of clinical trials and developmental programs with IMC-A12 and other therapeutics targeting IGF-IR is challenging. Perhaps the most formidable challenge is the initial selection of the precise cancer types and clinical settings that may be particularly amenable to single agent treatment, so that proof of principle can be established efficiently. With respect to the anticipated toxicities of treatment, the possibility that therapies directed against IGF-IR will lack sufficient specificity to avoid cotargeting the IR must be considered, and careful monitoring of glucose metabolism must be done despite the fact that dose-limiting toxicity involving increased blood glucose has not been observed in preclinical studies.
Phase 1 trials evaluating the safety and maximum-tolerated doses of IMC-A12 administered i.v. on weekly and biweekly schedules have been initiated in patients with refractory solid malignancies that are no longer responsive to standard therapy or for whom no standard therapy is available. The principal objectives of these studies include optimal dose finding for subsequent disease-directed evaluations, and toxicologic, pharmacologic, and immunologic assessments, as well as preliminary evaluations to detect anticancer activity. An early report involving the first 11 patients treated with weekly doses ranging from 3 to 10 mg/kg indicated that there were no consistent adverse effects (69). Noncompartmental pharmacokinetic analysis showed dose-dependent elimination and nonlinear exposure in the dosing range evaluated, which is consistent with saturable clearance mechanisms. To date, plasma half-life values at the 3 and 6 mg/kg dose levels averaged 148 and 209 h, and maximal IMC-A12 plasma concentrations of 333 and 415 µg/mL were noted. Furthermore, target trough concentrations of IMC-A12, as determined from preclinical studies in human tumor xenograft models, were achieved at the lower doses. Of note, two patients (one male patient with breast cancer and one patient with hepatocellular cancer) at the 3 mg/kg dose level experienced stable disease exceeding 9 months despite rapid disease progression prior to IMC-A12 treatment. Circulating tumor markers decreased in other patients who had stable disease of lesser duration. Doses, capable of simulating relevant pharmacologic conditions in preclinical studies and associated with preliminary evidence of clinical activity, have been recommended for IMC-A12 on weekly, every 2-week, and every 3-week schedules in disease-directed studies.
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Conclusions
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Anticancer strategies using antibodies to target growth factor receptors have emerged as a new class of effective clinical therapeutics, providing efficacy with low toxicity as an alternative or supplement to conventional cytotoxic therapy. The IGF-IR signaling pathway has been extensively shown to play a key role in the development and progression of many types of cancer, and both resistance and sensitivity to cytotoxic chemotherapeutics, hormonal agents, and targeted therapeutics can be modulated by the IGF-IR pathway, and visa versa. Experimental results support the concept that targeting IGF-IR may be beneficial in both early and late clinical stages in many diverse types of cancer. The fully human monoclonal antibody IMC-A12, which binds with high affinity to the IGF-IR, has shown encouraging preclinical results as a single agent and combined with other types of anticancer therapeutics. Because IMC-A12 specifically binds to the IGF-IR, and not to the IR, and robustly blocks receptor activation and downstream signaling, it may confer higher therapeutic indices in the clinic compared with nonspecific small molecule therapeutics. As clinical developmental programs progress, careful attention must be paid to the potential side effects, as well as the effects of dose and schedule on toxicity. Nevertheless, after many years of hypothesizing a unique role for anticancer therapeutics targeting IGF-IR signaling, the hypothesis is finally being evaluated in clinical trials of IMC-A12 and other agents targeting IGF-IR.
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Footnotes
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Presented at the Eleventh Conference on Cancer Therapy with Antibodies and Immunoconjugates, Parsippany, New Jersey, USA, October 12-14, 2006.
Note: All authors are employees of Imclone Systems Incorporated, which is involved in developing IMC-A12, the major therapeutic focus of the manuscript.
3 Ludwig DL, unpublished data. 
Received 5/ 8/07;
accepted 5/21/07.
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Abstract
Targeting IGF-IR as a...
