FCGR2A and FCGR3A Polymorphisms Associated With Clinical Outcome of Epidermal Growth Factor Receptor–Expressing Metastatic Colorectal Cancer Patients Treated With Single-Agent Cetuximab

Zhang, Wu; Gordon, Michael A.; Schultheis, Anne M.; Yang, Dongyun; Nagashima, Fumio; Azuma, Mizutomo; Chang, Heung-Moon; Borucka, E.; Lurje, Georg; Sherrod, Andy; Iqbal, Syma; Groshen, Susan; Lenz, Heinz‐Josef

doi:10.1200/jco.2006.08.8021

Cited by 442 publications

(319 citation statements)

References 29 publications

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“…More importantly, "knobs-intoholes" mutations located in the CH3 domain did not affect antibody effector functions, which are mediated mainly by the CH2 domain of antibodies as evidenced by the high ADCC activity of Bi-Ab. ADCC is an important mechanism of action for therapeutic antibodies in vivo (47)(48)(49). The result from our ADCC assay demonstrates that Bi-Ab has comparable or slightly enhanced ADCC activity compared with monospecific antibodies, m590 and trastuzumab, and the Comb.…”

Section: Discussionmentioning

confidence: 77%

Superior Antitumor Activity of a Novel Bispecific Antibody Cotargeting Human Epidermal Growth Factor Receptor 2 and Type I Insulin-like Growth Factor Receptor

Chen¹,

Zhang²,

Li³

et al. 2014

Molecular Cancer Therapeutics

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The humanized anti-HER2 monoclonal antibody (mAb) trastuzumab (Herceptin; Genentech) effectively inhibits human epidermal growth factor receptor 2 (HER2)-positive breast tumors. However, many patients responding to treatment often develop resistance. Cross-talk between type I insulin-like growth factor receptor (IGF-IR) and HER2 and elevated IGF-IR signaling have been implicated in tumor cell resistance to trastuzumab therapy. Previously, we reported that the anti-IGF-IR mAb m590 inhibits proliferation and migration of breast cancer MCF-7 cells in vitro. Here, we generated a "knobs-into-holes" bispecific antibody (Bi-Ab) against HER2 and IGF-IR by engineering trastuzumab and m590. We compared the effects of Bi-Ab treatment in vitro and in SKOV-3 HER2-and IGF-IR-overexpressing cancer xenograft mouse model with those of m590 and trastuzumab treatment alone or in combination. Bi-Ab effectively inhibited proliferation of HER2-and IGF-IR-overexpressing ovarian cancer SKOV-3 cells in vitro by ablating receptor phosphorylation and downstream PI3K/Akt and mitogen-activated protein kinase signaling. Bi-Ab more effectively inhibited cancer growth in SKOV-3 HER2-and IGF-IR-overexpressing cancer xenograft mouse model than m590 and trastuzumab alone or in combination. Mice bearing SKOV-3 HER2-and IGF-IR-overexpressing xenografts showed extensive and sustainable tumor regression when treated with Bi-Ab. Our results suggest that Bi-Ab has superior antitumor activity compared with monospecific antibodies, and cotargeting HER2 and IGF-IR may be clinically beneficial in minimizing the acquired resistance to trastuzumab therapy. Mol Cancer Ther; 13(1); 90-100. Ó2013 AACR.

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Section: Discussionmentioning

confidence: 77%

Superior Antitumor Activity of a Novel Bispecific Antibody Cotargeting Human Epidermal Growth Factor Receptor 2 and Type I Insulin-like Growth Factor Receptor

Chen¹,

Zhang²,

Li³

et al. 2014

Molecular Cancer Therapeutics

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“…Several studies have documented specific anti-tumor IgGs directed against autologous host tumor cells, 84,85 yet the role of endogenous tumor reactive antibodies and their subsequent activation of innate immune cells by Fc/FcR interactions remains a question. 80 However, the observation that genetic polymorphisms in FcγRIIa and FcγRIIIa correlate with the clinical outcome of patients with B-cell lymphoma (rituximab), 4,86 colorectal cancer (cetuximab) 3,87 and breast cancer (trastuzumab) 5 implicate a role for antibody Fc/FcγR interactions in cancer immune surveillance, at least with anti-cancer mAb therapeutics. A more recent study indicated that anti-cancer mAb therapies can function to augment endogenous antibody responses to tumor surface antigens, in particular the antigen HER2.…”

Section: Discussionmentioning

confidence: 99%

Cleavage of IgGs by proteases associated with invasive diseases

Brezski¹,

Jordan²

2010

mAbs

143

125

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“…This established that the ability of antibodies to reduce tumour burden was greatly reduced in the absence of immune cells expressing FcgRs. Secondly, colorectal, lymphoma and breast cancer patients carrying the polymorphic variants in the FcgRIIIa and FcgRIIa genes that encode for high affinity binding receptors for the Fc antibody segments, have the best clinical outcomes following antibody treatment (Weng and Levy, 2003;Zhang et al, 2007;Musolino et al, 2008).…”

mentioning

confidence: 99%

Humanised IgG1 antibody variants targeting membrane-bound carcinoembryonic antigen by antibody-dependent cellular cytotoxicity and phagocytosis

Ashraf

Umaña²,

Mössner³

et al. 2009

Br J Cancer

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BACKGROUND: The effect of glycoengineering a membrane specific anti-carcinoembryonic antigen (CEA) (this paper uses the original term CEA for the formally designated CEACAM5) antibody (PR1A3) on its ability to enhance killing of colorectal cancer (CRC) cell lines by human immune effector cells was assessed. In vivo efficacy of the antibody was also tested. METHODS: The antibody was modified using EBNA cells cotransfected with b-1,4-N-acetylglucosaminyltransferase III and the humanised hPR1A3 antibody genes. RESULTS: The resulting alteration of the Fc segment glycosylation pattern enhances the antibody's binding affinity to the FcgRIIIa receptor on human immune effector cells but does not alter the antibody's binding capacity. Antibody-dependent cellular cytotoxicity (ADCC) is inhibited in the presence of anti-FcgRIII blocking antibodies. This glycovariant of hPR1A3 enhances ADCC 10-fold relative to the parent unmodified antibody using either unfractionated peripheral blood mononuclear or natural killer (NK) cells and CEA-positive CRC cells as targets. NK cells are far more potent in eliciting ADCC than either freshly isolated monocytes or granulocytes. Flow cytometry and automated fluorescent microscopy have been used to show that both versions of hPR1A3 can induce antibody-dependent cellular phagocytosis (ADCP) by monocyte-derived macrophages. However, the glycovariant antibody did not mediate enhanced ADCP. This may be explained by the relatively low expression of FcgRIIIa on cultured macrophages. In vivo studies show the efficacy of glycoengineered humanised IgG1 PR1A3 in significantly improving survival in a CRC metastatic murine model. CONCLUSION: The greatly enhanced in vitro ADCC activity of the glycoengineered version of hPR1A3 is likely to be clinically beneficial.

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FCGR2A and FCGR3A Polymorphisms Associated With Clinical Outcome of Epidermal Growth Factor Receptor–Expressing Metastatic Colorectal Cancer Patients Treated With Single-Agent Cetuximab

Abstract: Our preliminary data suggest that these two polymorphisms may be useful molecular markers to predict clinical outcome in metastatic CRC patients treated with cetuximab and that they may indicate a role of ADCC of cetuximab.

Cited by 442 publications

References 29 publications

Superior Antitumor Activity of a Novel Bispecific Antibody Cotargeting Human Epidermal Growth Factor Receptor 2 and Type I Insulin-like Growth Factor Receptor

Superior Antitumor Activity of a Novel Bispecific Antibody Cotargeting Human Epidermal Growth Factor Receptor 2 and Type I Insulin-like Growth Factor Receptor

Cleavage of IgGs by proteases associated with invasive diseases

Humanised IgG1 antibody variants targeting membrane-bound carcinoembryonic antigen by antibody-dependent cellular cytotoxicity and phagocytosis

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