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

Abstract

(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.

Functional studies of E. faecalis RNase J2 and its role in virulence and fitness

“…In Bacillus subtilis the pyr operon is regulated by the first gene of the operon, pyrR, through an autogenous transcriptional attenuation mechanism [37]. However, the E .…”

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

“…Additionally, selective enhancement of FcγRIIB binding was used to generate an anti-CD137 agonist with increased agonistic activity in vitro 257 . Individual FcRs have also been shown to exhibit differential contributions to cellular functions; for example, it has been demonstrated that FcγRI was largely responsible for secretion of both anti-inflammatory IL-10 258 and pro-inflammatory cytokines 259 . A suggested implication of this findings was that macrophage-mediated ADCC and ADCP could potentially be uncoupled from antibody-dependent cytokine release (ADCR), a feat which was accomplished recently by Kinder et.…”

“…A suggested implication of this findings was that macrophage-mediated ADCC and ADCP could potentially be uncoupled from antibody-dependent cytokine release (ADCR), a feat which was accomplished recently by Kinder et. al., using an Fc-engineering approach to modulate cytokine release while leaving cell-killing activity intact 259 . The ability to selectively fine-tune or prevent cytokine release thus opens the possibility of limiting cytokine-related adverse events without losing effector capacity and tumoricidal activity.…”

Proteinase-nicked IgGs: an unanticipated target for tumor immunotherapy

“…The sources of the anti-hinge Abs have been AHAs isolated from human serum, 14 a monoclonal anti-hinge mAb, 48 immunization-derived immune responses to peptide analogs of the cleaved hinge, 47 and proteinase-resistant versions of a monoclonal anti-hinge mAb. 53 The anti-hinge antibodies bind to the cleaved primary antibodies on the cell surface to provide an intact hinge and Fc that are capable of restoring ADCC and complement against the cancer cells. (b) Quantitative assessments of ADCC by intact and single-cleaved trastuzumab and the anti-hinge mAb 2095–2 alone and in combination with the scIgG.…”