IgE Immunotherapy Against Cancer

Leoh, Lai Sum; Daniels‐Wells, Tracy R.; Penichet, Manuel L.

doi:10.1007/978-3-319-13725-4_6

Cited by 23 publications

(32 citation statements)

References 177 publications

(239 reference statements)

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“…Several of the Fc modifications are being validated in preclinical development and clinical trials and hence it is expected that more therapeutic antibodies with engineered Fc mutations will be approved soon. Beyond IgG, the class of choice for all the approved therapeutic antibodies used for oncologic applications, other classes of antibodies such as IgA ( 175 ) and IgE ( 176 ) are emerging as new options for cancer therapy. These new options, together with the outstanding progress in the development of antibody engineering methods to modify the V regions should lead to a profound impact in the therapy of cancer in the near future.…”

Section: Concluding Remarks and Future Developmentsmentioning

confidence: 99%

Progress and Challenges in the Design and Clinical Development of Antibodies for Cancer Therapy

Almagro¹,

et al. 2018

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The remarkable progress in engineering and clinical development of therapeutic antibodies in the last 40 years, after the seminal work by Köhler and Milstein, has led to the approval by the United States Food and Drug Administration (FDA) of 21 antibodies for cancer immunotherapy. We review here these approved antibodies, with emphasis on the methods used for their discovery, engineering, and optimization for therapeutic settings. These methods include antibody engineering via chimerization and humanization of non-human antibodies, as well as selection and further optimization of fully human antibodies isolated from human antibody phage-displayed libraries and immunization of transgenic mice capable of generating human antibodies. These technology platforms have progressively led to the development of therapeutic antibodies with higher human content and, thus, less immunogenicity. We also discuss the genetic engineering approaches that have allowed isotype switching and Fc modifications to modulate effector functions and bioavailability (half-life), which together with the technologies for engineering the Fv fragment, have been pivotal in generating more efficacious and better tolerated therapeutic antibodies to treat cancer.

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Section: Concluding Remarks and Future Developmentsmentioning

confidence: 99%

Progress and Challenges in the Design and Clinical Development of Antibodies for Cancer Therapy

Almagro¹,

et al. 2018

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“…Using recombinant monoclonal antibodies (mAb) of the IgE class for immunotherapy of cancer is an innovative approach that has shown promising results in vitro and in vivo. [1][2][3] MAbs for the treatment of cancer are typically designed as IgGs, but use of such molecules has drawbacks, including: 1) relatively low affinity for cognate Fcγ receptors; 2) short half-life in tissues; and 3) the expression of inhibitory Fcγ receptors (FcγRIIb) on immune cells in the tumor microenvironment (TME), which may limit the effector functions and potency of IgGs to promote immune surveillance against solid tumors. 4,5 In contrast, IgE displays up to 10,000-fold higher affinities for and slow dissociation from cognate Fcε receptors on IgE effector cells often found in the TME, lacks inhibitory FcRs, is retained for longer than IgG in tissues, and can exert immune surveillance in Th2-biased environments such as the TME.…”

Section: Introductionmentioning

confidence: 99%

In vivo safety profile of a CSPG4-directed IgE antibody in an immunocompetent rat model

Williams

Crescioli

Sow

et al. 2019

mAbs

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IgE monoclonal antibodies hold great potential for cancer therapy. Preclinical in vivo systems, particularly those in which the antibody recognizes the host species target antigen and binds to cognate Fc receptors, are often the closest approximation to human exposure and represent a key challenge for evaluating the safety of antibody-based therapies. We sought to develop an immunocompetent rat system to assess the safety of a rodent anti-tumor IgE, as a surrogate for the human therapeutic candidate. We generated a rat IgE against the human tumor-associated antigen chondroitin sulfate proteoglycan 4 (CSPG4) and cross-reactive for the rat antigen. We analyzed CSPG4 distribution in normal rat and human tissues and investigated the in vivo safety of the antibody by monitoring clinical signs and molecular biomarkers after systemic administration to immunocompetent rats. Human and rat CSPG4 expression in normal tissues were comparable. Animals receiving antibody exhibited transient mild to moderate adverse events accompanied by mild elevation of serum tryptase, but not of angiotensin II or cytokines implicated in allergic reactions or cytokine storm. In the long term, repeated antibody administration was well tolerated, with no changes in animal body weight, liver and kidney functions or blood cell counts. This model provides preclinical support for the safety profiling of IgE therapeutic antibodies. Due to the comparable antigen tissue distribution in human and rat, this model may also comprise an appropriate tool for proof-of-concept safety evaluations of different treatment approaches targeting CSPG4.

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“…However, several studies addressed this issue and concluded that systemic hypersensitivity reactions caused by tumor antigen-directed IgE antibodies may not occur in a therapeutic setting. Additionally, no evidence for systemic hypersensitivity reactions due to IgE antibody therapy was seen in various in vivo models (reviewed in [51]). As a result of these in vitro and in vivo observations, an ongoing phase I clinical trial evaluates the potential of IgE antibodies in cancer immunotherapy (NCT02546921).…”

Section: Igementioning

confidence: 99%

Antibody Isotypes for Tumor Immunotherapy

Kretschmer

Schwanbeck

Valerius

et al. 2017

Transfus Med Hemother

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Compared to the evolutionary diversity of antibody isotypes, the spectrum of currently approved therapeutic antibodies is biased to the human IgG1 isotype. Detailed studies into the different structures and functions of human isotypes have suggested that other isotypes than IgG1 may be advantageous for specific indications - depending on the complex interplay between the targeted antigen or epitope, the desired mode of action, the pharmacokinetic properties, and the biopharmaceutical considerations. Thus, it may be speculated that with the increasing number of antibodies becoming available against a broadening spectrum of target antigens, identification of the optimal antibody isotype for particular therapeutic applications may become critical for the therapeutic success of individual antibodies. Thus, investments into this rather unexplored area of antibody immunotherapy may provide opportunities for distinction in the increasingly busy ‘antibody space'. Therefore, IgG, IgA, IgE as well as IgM isotypes will be discussed in this review.

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IgE Immunotherapy Against Cancer

Cited by 23 publications

References 177 publications

Progress and Challenges in the Design and Clinical Development of Antibodies for Cancer Therapy

Progress and Challenges in the Design and Clinical Development of Antibodies for Cancer Therapy

In vivo safety profile of a CSPG4-directed IgE antibody in an immunocompetent rat model

Antibody Isotypes for Tumor Immunotherapy

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