Tumor localized agonistic anti-CD40 therapy and beyond

Eltahir, Mohamed; Persson, Helena; Mangsbo, Sara M.

doi:10.1080/14712598.2020.1713084

Cited by 5 publications

(5 citation statements)

References 19 publications

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“…Special attention is given on the concurrent modulation of the immune system. One example is anti-CD40 agonistic antibody therapy that involves CD8 + T cell-priming and T cell-mediated anti-tumor responses [ 185 ]. CD40 agonists bind to the CD40 receptor, a cell-surface member of the TNF receptor superfamily, expressed by APCs, including dendritic cells; once activated, dendritic cells activate T cells and prime them against tumors.…”

Section: Discussion—future Perspectivesmentioning

confidence: 99%

The Role of Tumor Microenvironment in Cancer Metastasis: Molecular Mechanisms and Therapeutic Opportunities

Neophytou

Panagi

Stylianopoulos

et al. 2021

Cancers

213

106

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The tumor microenvironment (TME) regulates essential tumor survival and promotion functions. Interactions between the cellular and structural components of the TME allow cancer cells to become invasive and disseminate from the primary site to distant locations, through a complex and multistep metastatic cascade. Tumor-associated M2-type macrophages have growth-promoting and immunosuppressive functions; mesenchymal cells mass produce exosomes that increase the migratory ability of cancer cells; cancer associated fibroblasts (CAFs) reorganize the surrounding matrix creating migration-guiding tracks for cancer cells. In addition, the tumor extracellular matrix (ECM) exerts determinant roles in disease progression and cancer cell migration and regulates therapeutic responses. The hypoxic conditions generated at the primary tumor force cancer cells to genetically and/or epigenetically adapt in order to survive and metastasize. In the circulation, cancer cells encounter platelets, immune cells, and cytokines in the blood microenvironment that facilitate their survival and transit. This review discusses the roles of different cellular and structural tumor components in regulating the metastatic process, targeting approaches using small molecule inhibitors, nanoparticles, manipulated exosomes, and miRNAs to inhibit tumor invasion as well as current and future strategies to remodel the TME and enhance treatment efficacy to block the detrimental process of metastasis.

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Section: Discussion—future Perspectivesmentioning

confidence: 99%

The Role of Tumor Microenvironment in Cancer Metastasis: Molecular Mechanisms and Therapeutic Opportunities

Neophytou

Panagi

Stylianopoulos

et al. 2021

Cancers

213

106

View full text Add to dashboard Cite

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“…The IgG2‐based Bi10‐1150 and 1150–2 were chosen for this experiment due to the uniform DC activation profile of the bispecific and parental antibodies and the superior T cell activation in vitro, along with literature supporting the IgG2 format for agonistic activity. [ 26–29 ] A mixture of UU30 and Bi10‐1150 or 1150–2 was injected to the same side hock that received the tghCD40 BMDCs (Figure 5B). Draining popliteal lymph node analysis after 72 h of treatment identified an average of 60% expansion of pmel‐1 (Thy1.1 + , CD3 + , CD8 + ) cells in the UU30/Bi10‐1150 group (Figure 5C–E).…”

Section: Resultsmentioning

confidence: 99%

“…The agonistic anti‐CD40 antibodies rely on the IgG2 format and the unique disulfide hinge for retained agonistic activity. [ 26–29 ] However, IgG1 formats are also employed, taking advantage of the FcγR interaction to deliver agonistic anti‐CD40 signaling. [ 26,50 ] While BiTag antibodies of IgG1 format (e.g., Bi1‐CP) appeared to retain their FcγRIIIA interaction in the SPR experiment, the human whole blood experiment indicated that the FcγRIIIA interaction was impaired, possibly by steric hindrance on cell surfaces by the presence of the scFv.…”

Section: Discussionmentioning

confidence: 99%

An Adaptable Antibody‐Based Platform for Flexible Synthetic Peptide Delivery Built on Agonistic CD40 Antibodies

Eltahir

Lord

Chourlia

et al. 2022

Advanced Therapeutics

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The agonistic potentials of therapeutic anti‐CD40 antibodies have been profiled in relation to antibody isotype and epitope specificity. Still, clinical impact relies on a well‐balanced clinical efficacy versus target‐mediated toxicity. As CD40‐mediated immune activation must rely on a combination of stimulation of antigen‐presenting cells (APCs) alongside antigen presentation, for efficient T cell priming, alternative approaches to improve the therapeutic outcome of CD40‐targeting strategies should focus on providing optimal antigen presentation together with CD40 stimulation. Herein, a bispecific antibody targeting CD40 as a means to deliver cargo (i.e., synthetic peptides) into APCs through a non‐covalent, high‐affinity interaction between the antibody and the cargo peptide, further referred to as the Adaptable Drug Affinity Conjugate (ADAC) technology, has been developed. The ADAC platform demonstrated a target‐specific CD4+ and CD8+ T cell expansion in vitro and significantly improved peptide‐specific CD8+ T cell proliferation in vivo. In addition, the strategy dramatically improved the in vitro and in vivo half‐life of the synthetic peptides. Future applications of ADAC involve pandemic preparedness to viral genetic drift as well as neoepitope vaccination strategies where the bispecific antibody is an off‐the‐shelf product, and the peptide antigen is synthesized based on next‐generation sequencing data mining.

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“…CD40-CD40L signaling can improve rapid generation of cytotoxic T lymphocyte (CTL), secretion of cytokines, and up-regulation of other costimulatory molecules, which represents a particularly promising approach to triggering antitumor response . Studies showed that anti-CD40 monoclonal antibodies (mAbs) could provide additional stimulation to DC in the absence of helper T cells . The combination of chemotherapy (to release tumor antigen) and anti-CD40 mAbs therapy could synergize to promote stronger T cell immunity .…”

Section: Mechanisms Of Action Of Immunomodulatory Therapeuticsmentioning

confidence: 99%

“…36 Studies showed that anti-CD40 monoclonal antibodies (mAbs) could provide additional stimulation to DC in the absence of helper T cells. 37 The combination of chemotherapy (to release tumor antigen) and anti-CD40 mAbs therapy could synergize to promote stronger T cell immunity. 38 In several advanced cancer patients, anti-CD40 mAbs were used to further enhance the role of chemotherapy agents (gemcitabine or paclitaxel), which showed more remarkable therapeutic activity than monotherapy.…”

Section: Mechanisms Of Action Of Immunomodulatory Therapeuticsmentioning

confidence: 99%

Nanomaterials as Smart Immunomodulator Delivery System for Enhanced Cancer Therapy

Yuan

Liu

Wang

et al. 2020

ACS Biomater. Sci. Eng.

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Immunomodulatory therapeutics, which is conducive to overcoming tumor tolerance and restoring normal immune responses, has been proposed as a promising approach for enhanced cancer therapy and clinical advancement. However, issues including cytokine syndrome, inefficient delivery, hepatic dysfunction, and severe adverse reactions remain to be resolved. It is particularly critical to develop delivery technologies to overcome these limitations and further improve antitumor efficacy. With the continuous development of materials science, biomaterials have been widely used in the field of cancer treatment and have also provided exciting solutions to overcome the bottleneck of immunomodulatory therapeutics. A range of biomaterials, especially nanomaterials, has been developed as a local immunomodulatory platform to enhance targeted delivery, maintain drug stability, and reduce toxicity and side effects. In addition to single immunomodulatory therapeutics, nanomaterials have been demonstrated to possess significant potential in immunomodulatory therapeutics-based synergistic therapies, especially in combination with phototherapy, radiotherapy, chemotherapy, and immune checkpoint blockade. In this review, as background to the discussion of immunomodulatory therapeutics, we first described the mechanisms of action of multiple immunomodulators and discussed their current targeting agents. On this basis, we highlighted the latest advances in the use of nanomaterials-assisted immunomodulatory therapeutics and combination therapy to enhance anticancer immunity. In addition, current challenges and further promises for immunomodulatory therapeutics were also presented.

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Tumor localized agonistic anti-CD40 therapy and beyond

Cited by 5 publications

References 19 publications

The Role of Tumor Microenvironment in Cancer Metastasis: Molecular Mechanisms and Therapeutic Opportunities

The Role of Tumor Microenvironment in Cancer Metastasis: Molecular Mechanisms and Therapeutic Opportunities

An Adaptable Antibody‐Based Platform for Flexible Synthetic Peptide Delivery Built on Agonistic CD40 Antibodies

Nanomaterials as Smart Immunomodulator Delivery System for Enhanced Cancer Therapy

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