Rationale for the development of IMC‐3G3, a fully human immunoglobulin G subclass 1 monoclonal antibody targeting the platelet‐derived growth factor receptor α

Abstract

A large body of evidence suggests that the platelet-derived growth factor (PDGF) family and associated receptors are potential targets in oncology therapeutic development because of their critical roles in the proliferation and survival of various cancers and in the regulation and growth of the tumor stroma and blood vessels. Several small molecules that nonspecifically target the PDGF signaling axis are in current use or development as anticancer therapies. However, for the majority of these agents, PDGF and its receptors are neither the primary targets nor the principal mediators of anticancer activity. IMC-3G3, a fully human monoclonal antibody of the immunoglobulin G subclass 1, specifically binds to the human PDGF receptor a (PDGFRa) with high affinity and blocks PDGF ligand binding and PDGFRa activation. The results of preclinical studies and the frequent expression of PDGFRa in many types of cancer and in cancer-associated stroma support a rationale for the clinical development of IMC-3G3. Currently, IMC-3G3 is being evaluated in early clinical development for patients with several types of solid malignancies. Cancer 2010;116(4 suppl):1018-26.

Pharmacokinetics and systems pharmacology of monoclonal antibody olaratumab for inoperable soft tissue sarcoma

“…Indeed, PDGFRα has also been implicated in other malignancies with strong expression of PDGFRα in ovarian tumors [29] ; also, 70% of hepatocellular carcinoma tissues exhibit elevated PDGFRα levels [30] . In a human tumor array, PDGFRα expression is observed in about 95% of osteosarcomas and chondrosarcomas [5] . Table 1 summarizes PDGFR expression in various tumors and cell lines.…”

“…Olaratumab includes two heavy chains (gamma-1) and two light chains (kappa), twelve intra-chain disulfide bonds, four inter-chain disulfide bonds, and two glycosylation sites including one at Asn30 in the Fab region of the heavy chain and one at Asn307 in the Fc region of the heavy chain [25] . exhibiting potential inhibition of vasculature, tumor, and stroma [5] . Olaratumab may also act by promoting receptor internalization of PDGFRα with a consequent decrease in intracellular signaling [31] .…”

“…Given the high affinity (K D = 0.04 n mol/L or 40 pmol/L) of olaratumab binding to PDGFRα, it blocks both PDGF-AA and PDGF-BB ligands from binding to PDGFRα and does not exhibit cross-reactivity with isoform PDGFRβ or with murine PDGFRα [5,32] . The affinity constant K D = K off /K on is determined by BIAcore analysis [32] .…”

“…Given its discovery at ImClone, olaratumab has also been alternatively known in the literature as IMC-3G3 [5] . Sarcomas, which are rare tumors arising or differentiated from mesodermal tissues, are categorized mainly into two groups-soft tissue sarcomas and bone tissue sarcomas-both of which have different staging and therapeutic approaches [6] .…”

Trial Watch: Monoclonal antibodies in cancer therapy

“…Necitumumab (IMC-11F8) is a fully human IgG1 mAb targeting the epidermal growth factor receptor growth of tumor stroma and blood vessels. 93 Blocking PDGFα with olaratumab on neoplastic (but not stromal) cells delayed tumor progression and reduced the size of skeletal metastases in preclinical models of prostate cancer. 94 Now, olaratumab is being evaluated, either alone or combined with conventional chemotherapeutics, in 7 phase I-II trials against a variety of solid tumors ( Table 4).…”