IMC-A12,aHumanIgG 1 Monoclonal Antibody tothe Insulin- LikeGrowthFactorIReceptor EricK.Rowinsky, 1 HagopYoussoufian, 1 JamesR.Tonra, 2 PhillipSolomon, 2 DouglasBurtrum, 2 andDaleL.Ludwig 2 Abstract Targeted monoclonalantibody therapy is animportant strategy in cancer therapeutics. Among the most promising characteristics of therapeutic targets are those that modulate the growth andsurvivalofmalignantneoplasmsandtheirsensitivitytoanticancertherapies.Theinsulin-like growthfactor-Ireceptor (IGF-IR) isoverexpressedinmany types of solidandhematopoietic malignancies,andhasbeenimplicatedasaprincipalcauseofheightenedproliferativeandsurvival signaling.IGF-IRhasalsobeenshowntoconferresistancetocytotoxic,hormonal,andtargeted therapies,suggestingthattherapeuticstargetingIGF-IRmaybeeffectiveagainstabroadrangeof malignancies.IMC-A12(ImCloneSystemsIncorporated),afullyhumanmonoclonalIgG 1 antibody thatbinds withhighaffinity to the IGF-IR, inhibits ligand-dependent receptor activationand downstream signaling. IMC-A12 also mediates robustinternalizationand degradationof the IGF-IR. Inhumantumor xenograft models, IGF-IR blockade by IMC-A12 results inrapidand profoundgrowthinhibitionofcancersofthebreast,lung,colon,andpancreas,andmanyother neoplasms.Althoughpromisingsingle-agentactivityhasbeenobserved,themostimpressive effects of targeting the IGF-IR with IMC-A12 have beennoted when this agent was combined with cytotoxic agents orother targeted therapeutics.The results with IMC-A12 to date suggest thatitmaybeaneffectivetherapeuticinadiversearrayofoncologicindications. 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 neuro- developmental 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). TargetingIGF-IRasaTherapeuticStrategy againstCancer The IGF-IR and its ligands IGF-I and IGF-II have been implicated as playing key roles in the development, mainte- nance, and progression of cancer (3, 5, 9–15). IGF-IR activation can stimulate cellular proliferation and differentia- tion 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: 1 DepartmentofClinical Researchand RegulatoryAffairs, ImClone Systems Incorporated, Branchburg, NewJersey and 2 Departmentof Research,ImCloneSystemsIncorporated,NewYork,NewYork Received5/8/07;accepted5/21/07. Presented at the Eleventh Conference on CancerTherapy with Antibodies and Immunoconjugates,Parsippany,NewJersey,USA,October12-14,2006. Note: Allauthors are employees of Imclone Systems Incorporated, whichis involvedindevelopingIMC-A12,themajortherapeuticfocusofthemanuscript. Requests for reprints: Eric K. Rowinsky, ImCloneSystems Incorporated, 33 ImCloneDrive,Branchburg,NJ08876.Phone: 908-203-6912;Fax: 908-231- 9885;E-mail:eric.rowinsky@imclone.com. F 2007AmericanAssociationforCancerResearch. doi:10.1158/1078-0432.CCR-07-1109 www.aacrjournals.org ClinCancerRes2007;13(18Suppl)September15,2007 5549s Downloaded from http://aacrjournals.org/clincancerres/article-pdf/13/18/5549s/1971989/5549s.pdf by guest on 17 June 2022