Monoclonal Antibody against Cell Surface GRP78 as a Novel Agent in Suppressing PI3K/AKT Signaling, Tumor Growth, and Metastasis

Abstract

Purpose The ER chaperone GRP78 translocates to the surface of tumor cells and promotes survival, metastasis, and resistance to therapy. An oncogenic function of cell surface GRP78 has been attributed to the activation of phosphoinositide 3-kinase (PI3K) pathway. We intend to use a novel anti-GRP78monoclonal antibody (MAb159) to attenuate PI3K signaling and inhibit tumor growth and metastasis. Experimental Design MAb159 was characterized biochemically. Anti-tumor activity was tested in cancer cell culture, tumor xenograft models, tumor metastasis models, and spontaneous tumor models. Cancer cells and tumor tissues were analyzed for PI3K activity. MAb159 was humanized and validated for diagnostic and therapeutic application. Results MAb159 specifically recognized surface GRP78, triggered GRP78 endocytosis, and localized to tumors but not normal organs in vivo. MAb159 inhibited tumor cell proliferation and enhanced tumor cell death both in vitro and in vivo. In MAb159 treated tumors, PI3K signaling was inhibited without compensatory MAPK pathway activation. Furthermore, MAb159 halted or reversed tumor progression in the spontaneous PTEN loss driven prostate and leukemia tumor models, and inhibited tumor growth and metastasis in xenograft models. Humanized MAb159, which retains high affinity, tumor specific localization, and the anti-tumor activity, was non-toxic in mice and had desirable pharmacokinetics. Conclusions GRP78 specific antibody MAb159 modulates PI3K pathway and inhibits tumor growth and metastasis. Humanized MAb159 will enter human trials shortly.

GRP78 haploinsufficiency suppresses acinar-to-ductal metaplasia, signaling, and mutant Kras -driven pancreatic tumorigenesis in mice

“…Subsequently, it was demonstrated that the cell-surface form of GRP78 (scGRP78) complexes with PI3K to promote phosphatidylinositol (3-5)-trisphosphate formation (18). Targeting csGRP78 with a monoclonal antibody led to suppression of AKT signaling and tumor growth (45,46). CsGRP78 is also an obligatory binding partner for Cripto, a GPI-anchored cell-surface protein and an upstream regulator of the TGFβ pathway and of AKT (47,48).…”

Nanoparticles inhibit cancer cell invasion and enhance antitumor efficiency by targeted drug delivery via cell surface-related GRP78

“…24,25 Blockade of cell surface GRP78 inhibited the proliferation and induced apoptosis in melanoma and prostate cancer. 26,27 Inhibition of cell surface GRP78 inhibited the tumor invasion and metastasis in hepatocellular carcinoma and colorectal cancer cell. [28][29][30] Nowadays, cell surface GRP78 is regarded as a potential target for the targeted therapy of many human cancers.…”

In vivo amelioration of endogenous antitumor autoantibodies via low-dose P4N through the LTA4H/activin A/BAFF pathway

“…However, the natural GRP78 IgM has a low binding affinity and a restricted binding repertoire. To resolve this problem, a monoclonal anti-GRP78 antibody, mAb159, has been developed, and it can inhibit tumor growth and metastasis by modulating the PI3K pathway (56).…”

“…Passive transfer of antitumor antibodies offers a more efficient therapeutic modality. For example, a humanized monoclonal anti-GPR78 antibody (mAb159) that has shown inhibitory activity for CRC (56) has been developed. Patients with normal immunity who have cancer may negatively select out B cells with high activities against autoantigens, resulting in lowactivity EAAs.…”