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Review
. 2016 Sep;8(9):1097-117.
doi: 10.2217/imt-2016-0021.

Anti-GD2 mAbs and next-generation mAb-based agents for cancer therapy

Zulmarie Perez Horta  1 , Jacob L Goldberg  1 , Paul M Sondel  1   2
Affiliations
Review

Anti-GD2 mAbs and next-generation mAb-based agents for cancer therapy

Zulmarie Perez Horta et al. Immunotherapy. 2016 Sep.

"V体育官网" Erratum in

  • Erratum.
    [No authors listed] [No authors listed] Immunotherapy. 2016 Nov;8(11):1349. doi: 10.2217/imt-2016-0021e1. Epub 2016 Oct 12. Immunotherapy. 2016. PMID: 27730843 Free PMC article. No abstract available.

"V体育平台登录" Abstract

Tumor-specific monoclonal antibodies (mAbs) have demonstrated efficacy in the clinic, becoming an important approach for cancer immunotherapy. Due to its limited expression on normal tissue, the GD2 disialogangloside expressed on neuroblastoma cells is an excellent candidate for mAb therapy VSports手机版. In 2015, dinutuximab (an anti-GD2 mAb) was approved by the US FDA and is currently used in a combination immunotherapeutic regimen for the treatment of children with high-risk neuroblastoma. Here, we review the extensive preclinical and clinical development of anti-GD2 mAbs and the different mechanisms by which they mediate tumor cell killing. In addition, we discuss different mAb-based strategies that capitalize on the targeting ability of anti-GD2 mAbs to potentially deliver, as monotherapy, or in combination with other treatments, improved antitumor efficacy. .

Keywords: cancer immunotherapy; monoclonal antibodies; neuroblastoma V体育安卓版. .

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Conflict of interest statement

Financial & competing interests disclosure

This research was supported by Hyundai Hope on Wheels Grant; Midwest Athletes Against Childhood; Stand Up 2 Cancer; The St. Baldrick’s Foundation; American Association of Cancer Research; University of Wisconsin-Madison Carbone Cancer Center; and supported in part by Public Health Service Grants CA21115, CA23318, CA66636, CA180820, CA180794, CA21076, CA180799, CA14958, CA180816, CA166105 and CA197078; from the National Cancer Institute. The Advanced Opportunity Fellowship through SciMed Graduate Research Scholars and the Molecular Bioscience Training Grant (MBTG) T32 GM07215 at University of Wisconsin – Madison, provided funding for ZP Horta and The Howard Hughes Medical Scholars Fellowship Program provided funding for JL Goldberg. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed V体育ios版.

No writing assistance was utilized in the production of this manuscript.

Figures

<b>Figure 1.</b>
Figure 1.. Effector mechanisms of anti-GD2 mAbs and mAb-based approaches.
Binding of naked anti-GD2 mAbs to the surface of NBL cells leads to three possible effector mechanisms: the recruitment of FCR expressing effector cells such as NK cells and granulocytes to mediate ADCC and monocytes and macrophages to mediate phagocytosis; induction of CDC by binding of C1q to the mAb, subsequent activation of the complement cascade and delivery of MAC to the tumor cell membrane; and direct cytotoxicity by crosslinking of the mAbs and the induction of apoptosis. IL2-based immunocytokines concentrate IL2 at the tumor site and lead to the activation of effector cells for tumor cell killing via engagement of both their IL2R and FCRs. Radiolebled mAbs serve as markers for radioimmunodetection and can deliver tumoricidal doses of radiation to the tumor cells for cell death. Immunotoxins and drug conjugates deliver different agents to the cell membrane where they are internalized allowing the intracellular release of the toxic cargo leading to subsequent cell death. CAR T cells have been ex vivo engineered to recognize the tumor antigen and lead to tumor cell lysis. Bispecific mAbs exist in various formats, such as hybrid bifunctional mAbs with two different antigen-specific regions or as BITE with the main goal of simultaneously engaging tumor antigen and costimulatory molecules, such as CD3 to redirect T cells for tumor lysis. ADCC: Antibody-dependent cell cytotoxicity; BITE: Bispecific T-cell engagers; CAR: Chimeric antigen receptor; CDC: Complement-dependent cytotoxicity; FCR: Fc-receptor; IL2R: IL2 receptor; mAb: Monoclonal antibody; MAC: Membrane attack complex.
<b>Figure 2.</b>
Figure 2.. Progression-free survival over two decades for 169 patients with stage 4 neuroblastoma in first remission after consecutive immunotherapy regimens.
3F8 alone (regimen A – HR; n = 43), 3F8 + intravenous GM-CSF + CRA (regimen B – HR; n = 41) and 3F8 + subcutaneous GM-CSF + CRA (regimen C – HR; n; = 57 and regimen C – UHR; n = 28); p = 0.018 (derived from log-rank test to compare progression-free survival among these four groups). CRA: 13-cis-retinoic acid; HR: High risk; UHR: Ultra high risk. Adapted with permission from [41] © American Society of Clinical Oncology (2012). All rights reserved.
<b>Figure 3.</b>
Figure 3.. Event-free survival for 226 patients randomized into the treatment groups.
13-cis-retinoic acid (CRA) alone (standard therapy) versus immunotherapy (ch14.18 monoclonal antibody + GM-CSF + IL-2 + CRA) for high-risk neuroblastoma. Data are shown for event-free survival for all 226 patients. The estimated survival (±SE) at 2 years is indicated in the plot. Adapted with permission from [66] © Massachusetts Medical Society (2010). Reprinted with permission from Massachusetts Medical Society.
<b>Figure 4.</b>
Figure 4.. Development of an anti-anti-idiotypic monoclonal antibodies network.
The α-GD2 therapeutic mAb (green) acts as an antigen, eliciting the production of an α-id mAb (red) that recognizes the antigen-binding site of the α-GD2 mAb. This α-id mAb mimics the structure of GD2 leading to the generation of an anti-α-id mAb (purple) with parental antigenic specificity capable of recognizing the antigen-binding site of the α-id mAb and the original antigen, GD2.
<b>Figure 5.</b>
Figure 5.. Combination of radiation therapy and intratumoral injection of anti-GD2 monoclonal antibodies as an ‘in situ’ vaccine to induce an adaptive immune response.
Pretreatment with palliative doses of radiation therapy leads to the elimination of T regulatory cells and immunogenic tumor cell death. Followed by mAb/IL2 therapy, which facilitates tumor cytotoxicity and creates a favorable environment for antigen presentation and the induction of adaptive immunity with the creation of long-term tumor-specific memory. ADCC: Antibody-dependent cell cytotoxicity; APC: Antigen-presenting cell; CTL: Cytotoxic T lymphocyte; FCR: Fc-receptor; IL2R: IL2-receptor; MHC: Major histocompatibility complex; NBL: Neuroblastoma; NK cell: Natural killer cell; TCR: T cell receptor; Treg: T regulatory cell.
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