Impact of tumour microenvironment and Fc receptors on the activity of immunomodulatory antibodies

Furness, Andrew J.S.; Vargas, Frederick Arce; Peggs, Karl S.; Quezada, Sergio A.

doi:10.1016/j.it.2014.05.002

Cited by 94 publications

(81 citation statements)

References 66 publications

(95 reference statements)

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“…Our understanding of Fc-FcR interactions and their involvements in numerous biological processes, however, is far from complete, and their complexities are only now beginning to be unraveled. Overviews of Fc-FcR interactions and their role in mAb-based cancer therapy (specifically, their contributions to treatment efficacy) are available 7, 8, 180, 189, 190 .…”

Section: Mechanistic Contributions Of Fc-fcr Interactionsmentioning

confidence: 99%

“…The authors propose that the constrained disulfide hinge configuration facilitates uniquely compact divalent receptor clustering and thereby the induction of costimulatory signaling 209 . On the other hand, activating FcR are required to enable other TNFR agonists, such as GITR 197 , CD27 210 and CD134 211 , to deplete intratumoral Tregs (as with anti-CTLA-4 mAbs 78, 196, 197 ), implicating innate effector mechanisms (reviewed in 189 and shown in Table 4). Whether activating or inhibitory FcR are involved in the mechanism(s) underlying immunomodulatory agonist-induced boosting of initial antigen-priming in lymphoid organs, however, remains to be determined in vivo .…”

Section: Mechanistic Contributions Of Fc-fcr Interactionsmentioning

confidence: 99%

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Enhancing the safety of antibody-based immunomodulatory cancer therapy without compromising therapeutic benefit: Can we have our cake and eat it too?

Ryan

Wasser

Adler

et al. 2016

Expert Opinion on Biological Therapy

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Introduction Monoclonal antibodies (mAbs) targeting checkpoint inhibitors have demonstrated clinical benefit in treating patients with cancer and have paved the way for additional immune-modulating mAbs such as those targeting costimulatory receptors. The full clinical utility of these agents, however, is hampered by immune-related adverse events (irAEs) that can occur during therapy. Areas covered We first provide a general overview of tumor immunity, followed by a review of the two major classes of immunomodulatory mAbs being developed as cancer therapeutics: checkpoint inhibitors and costimulatory receptor agonists. We then discuss therapy-associated adverse events. Finally, we describe in detail the mechanisms driving their therapeutic activity, with an emphasis on interactions between antibody fragment crystallizable (Fc) domains and Fc receptors (FcR). Expert Opinion Given that Fc-FcR interactions appear critical in facilitating the ability of immunomodulatory mAbs to elicit both therapeutically useful as well as adverse effects, the engineering of mAbs that can effectively engage their targets while limiting interaction with FcRs might represent a promising future avenue for developing the next generation of immune-enhancing tumoricidal agents with increased safety and retention of efficacy.

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Section: Mechanistic Contributions Of Fc-fcr Interactionsmentioning

confidence: 99%

Section: Mechanistic Contributions Of Fc-fcr Interactionsmentioning

confidence: 99%

Enhancing the safety of antibody-based immunomodulatory cancer therapy without compromising therapeutic benefit: Can we have our cake and eat it too?

Ryan

Wasser

Adler

et al. 2016

Expert Opinion on Biological Therapy

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“…5 Furthermore, it has become increasingly apparent that antibody engagement of select FcgRs can drive efficacy for both proapoptotic and immune-modulatory antibodies. [6][7][8][9][10][11] Human FcgRs are typically divided into the activating FcgRs (e.g., FcgRI, FcgRIIa, and FcgRIIIa), which contain immunoreceptor tyrosine-based activation motifs (ITAM), and the inhibitory FcgRIIb, which contains an immunoreceptor tyrosine-based inhibitory motif (ITIM). 12 Both FcgRIIa and FcgRIIIa are further subdivided into high affinity polymorphisms (i.e., H131 and V158, respectively) and low affinity polymorphisms (i.e., R131 and F158, respectively).…”

Section: Introductionmentioning

confidence: 99%

An Fc engineering approach that modulates antibody-dependent cytokine release without altering cell-killing functions

Kinder

Greenplate

Strohl

et al. 2015

mAbs

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(2015) An Fc engineering approach that modulates antibodydependent cytokine release without altering cell-killing functions, mAbs, 7:3, 494-504, DOI: 10.1080DOI: 10. /19420862.2015 To link to this article: https://doi.org/10. 1080/19420862.2015 Cytotoxic therapeutic monoclonal antibodies (mAbs) often mediate target cell-killing by eliciting immune effector functions via Fc region interactions with cellular and humoral components of the immune system. Key functions include antibody-dependent cell-mediated cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), and complement-dependent cytotoxicity (CDC). However, there has been increased appreciation that along with cell-killing functions, the induction of antibody-dependent cytokine release (ADCR) can also influence disease microenvironments and therapeutic outcomes. Historically, most Fc engineering approaches have been aimed toward modulating ADCC, ADCP, or CDC. In the present study, we describe an Fc engineering approach that, while not resulting in impaired ADCC or ADCP, profoundly affects ADCR. As such, when peripheral blood mononuclear cells are used as effector cells against mAb-opsonized tumor cells, the described mAb variants elicit a similar profile and quantity of cytokines as IgG1. In contrast, although the variants elicit similar levels of tumor cell-killing as IgG1 with macrophage effector cells, the variants do not elicit macrophage-mediated ADCR against mAb-opsonized tumor cells. This study demonstrates that Fc engineering approaches can be employed to uncouple macrophage-mediated phagocytic and subsequent cell-killing functions from cytokine release.

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“…For example, given recent data suggesting that anti-CTLA-4 antibody leads to cancer regression by inducing the selective depletion of intratumoral Treg cells and that Treg cell depletion is dependent on the presence of Fc-receptor-expressing myeloid cells (Furness et al, 2014), it will be important to determine whether anti-CTLA-4 induces Treg cell depletion within TA-TLSs. Moreover, given the emerging concept that ''T-cell-inflamed'' tumors might be more responsive to immunebased therapy (Gajewski et al, 2013), it will be interesting to determine whether therapeutic manipulation could be used for inducing the formation or expansion of TA-TLSs and thereby augmenting the immune presence within the tumor.…”

Section: Cells Regulatory T (Treg) Cells B Cells and High Endothelmentioning

confidence: 99%

Close Encounters of the Tertiary Kind

Lee

Savage

2015

Immunity

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Impact of tumour microenvironment and Fc receptors on the activity of immunomodulatory antibodies

Cited by 94 publications

References 66 publications

Enhancing the safety of antibody-based immunomodulatory cancer therapy without compromising therapeutic benefit: Can we have our cake and eat it too?

Enhancing the safety of antibody-based immunomodulatory cancer therapy without compromising therapeutic benefit: Can we have our cake and eat it too?

An Fc engineering approach that modulates antibody-dependent cytokine release without altering cell-killing functions

Close Encounters of the Tertiary Kind

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