Molecular mechanisms involved in activity of h7C10, a humanized monoclonal antibody, to IGF‐1 receptor

Abstract

IGF-1 receptor (IGF-1R) plays a key role in the development of numerous tumors. Blockade of IGF-1R axis using monoclonal antibodies constitutes an interesting approach to inhibit tumor growth. We have previously shown that h7C10, a humanized anti-IGF-1R Mab, exhibited potent antitumor activity in vivo. However, mechanisms of action of h7C10 are still unknown. Here, we showed that h7C10 inhibited IGF-1-induced IGF-1R phosphorylation in a dose-dependent manner. Also, h7C10 abolished IGF-1-induced activation of PI3K/AKT and MAPK pathways. Cell cycle progression and colony formation were affected in the presence of h7C10 probably because of the inhibition of IGF-1-induced cyclin D1 and E expression. In addition, we demonstrated that h7C10 induced a rapid IGF-1R internalization leading to an accumulation into cytoplasm resulting in receptor degradation. Using lysosome and proteasome inhibitors, we observed that the IGF-1R aand b-chains could follow different degradation routes. Thus, we demonstrated that antitumoral properties of h7C10 are the result of IGF-1-induced cell signaling inhibition and down-regulation of IGF-1R level suggesting that h7C10 could be a candidate for therapeutic applications. '

A Phase I Pharmacokinetic and Pharmacodynamic Study of Dalotuzumab (MK-0646), an Anti-Insulin-like Growth Factor-1 Receptor Monoclonal Antibody, in Patients with Advanced Solid Tumors

“…Most notably, we observed significant reductions in IGF-1R protein expression in tumor and skin, consistent with the known induction of IGF-1R internalization and degradation that follows dalotuzumab binding to IGF-1R (23,24). Decreased IGF-1R signaling was also achieved, as indicated by significant on-therapy decreases in tumor pS6, pEIF4G, and Ki67 expression.…”

“…As with other mAbs targeted at cell-surface receptors, binding of dalotuzumab to its target (IGF-1R) triggers receptor-mediated endocytosis (23). The PK behavior of dalotuzumab is thus expected to conform to a pattern of target-mediated disposition such that low doses insufficient to saturate the target will produce clearance kinetics dominated by high-affinity binding of dalotuzumab to its target (followed by its irreversible internalization into target cells) and high doses will produce kinetics associated with FcRn-mediated protection of dalotuzumab from intracellular degradation (followed by its release into the plasma and/or interstitial space; ref.…”

“…Dalotuzumab binds to IGF-1R with a K d of approximately 1 nmol/L, induces receptor internalization and degradation, and inhibits IGF-1-and IGF-2-mediated cell proliferation, IGF-1R autophosphorylation, and AKT phosphorylation (23,24).…”

Polyubiquitination of Insulin-like Growth Factor I Receptor (IGF-IR) Activation Loop Promotes Antibody-induced Receptor Internalization and Down-regulation

“…However, there are several intermediate steps, such as receptor internalization and trafficking, before IGF-IR becomes accessible to the proteasomal and lysosomal degradation machineries (30,34). We therefore examined internalization of h10H5 by all five ubiquitination-defective IGF-IR mutants in RϪ cells by immunofluorescence.…”

Внутриклеточные Протеолитические Системы: Новый Класс Маркеров Для Ранней Диагностики И Прогноза Течения Злокачественных Опухолей

“…Многие ядерные белки, опосредующие программируемую клеточную гибель, являются субстра-тами для протеасом: транскрипционные факторы (c-Fos, c-Myc, AP-1), опухолевый супрессор p53, ингибитор NFkB IkB, белки, контролирующие клеточный цикл, белки семейства Bcl-2, белки, контролирующие активность ка-спаз (IAPs) и участвующие в проведении проаптотическо-го сигнала (cFLIP) [13]. Описано участие протеасом в ре-гуляции доступности эстрогеновых рецепторов, и, кроме того, в разрушении рецепторов прогестерона, в снижении экспрессии рецепторов EGFR и HER-2 / neu, участие в де-градации рецепторов инсулиноподобных факторов роста гормонов [14][15][16]. Наши данные показывают, что в опухо-левой ткани молочной железы активность и состав проте-асом варьирует в зависимости от наличия или отсутствия в них рецепторов эстрогенов и прогестерона [17].…”