Membrane-Proximal Epitope Facilitates Efficient T Cell Synapse Formation by Anti-FcRH5/CD3 and Is a Requirement for Myeloma Cell Killing

Li, Ji; Stagg, Nicola J.; Johnston, Jennifer; Harris, Michael J.; Menzies, Sam A.; DiCara, Danielle; Clark, Vanessa; Hristopoulos, Maria; Cook, Ryan; Slaga, Dionysos; Nakamura, Rin; Mccarty, L. P.; Sukumaran, Siddharth; Luis, Elizabeth; Ye, Zhengmao; Wu, Thomas D.; Sumiyoshi, Teiko; Danilenko, Dimitry M.; Lee, Genee Y.; Tótpál, Klára; Ellerman, Diego; Hötzel, Isidro; James, John R.; Junttila, Teemu T.

doi:10.1016/j.ccell.2017.02.001

Cited by 225 publications

(296 citation statements)

References 23 publications

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“…2,33,53 The exact mechanism for how T-cell redirecting bsAbs trigger T cell activation and subsequent target cell killing has yet to be elucidated, but some bsAb architectures and epitopes appear to be more potent than others. 31,53,54 Taken together, these findings support the mechanistic nature and biological relevance of our TBE model.…”

Section: Discussionsupporting

confidence: 76%

“…In doing so, our TBE model was able to capture the in vitro cytotoxicity data at various effector cell concentrations using one single intrinsic engagement potency value EC 50 (Table 1, S1, and S2, Figure 2, S2, 3e and 3f), suggesting that the intrinsic engagement potency of a bsAb, i.e., the number of TBE complexes between one effector cell and one target cell sufficient to activate the engaged T cells, is a critical parameter for assessing T-cell redirecting bsAb-mediated target cell killing. The EC 50 for a T-cell redirecting bsAb is expected to be determined by CD3 and target receptor binding epitopes, 53,54 the bsAb architecture, 31 and the sensitivity of individual target cells to T cell killing (Tables 1 and 2, Figure 2 and S2) . 2,33,53 The exact mechanism for how T-cell redirecting bsAbs trigger T cell activation and subsequent target cell killing has yet to be elucidated, but some bsAb architectures and epitopes appear to be more potent than others.…”

Section: Discussionmentioning

confidence: 99%

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Development of a Target cell-Biologics-Effector cell (TBE) complex-based cell killing model to characterize target cell depletion by T cell redirecting bispecific agents

Jiang

Chen

Carpenter

et al. 2018

mAbs

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T-cell redirecting bispecific antibodies (bsAbs) or antibody-derived agents that combine tumor antigen recognition with CD3-mediated T cell recruitment are highly potent tumor-killing molecules. Despite the tremendous progress achieved in the last decade, development of such bsAbs still faces many challenges. This work aimed to develop a mechanism-based pharmacokinetic/pharmacodynamic (PK/PD) modeling framework that can be used to assist the development of T-cell redirecting bsAbs. A Target cell-Biologics-Effector cell (TBE) complex-based cell killing model was developed using in vitro and in vivo data, which incorporates information on binding affinities of bsAbs to CD3 and target receptors, expression levels of CD3 and target receptors, concentrations of effector and target cells, as well as respective physiological parameters. This TBE model can simultaneously evaluate the effect of multiple system-specific and drug-specific factors on the T-cell redirecting bsAb exposure–response relationship on a physiological basis; it reasonably captured multiple reported in vitro cytotoxicity data, and successfully predicted the effect of some key factors on in vitro cytotoxicity assays and the efficacious dose of blinatumomab in humans. The mechanistic nature of this model uniquely positions it as a knowledge-based platform that can be readily expanded to guide target selection, drug design, candidate selection and clinical dosing regimen projection, and thus support the overall discovery and development of T-cell redirecting bsAbs.

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Section: Discussionsupporting

confidence: 76%

Section: Discussionmentioning

confidence: 99%

Development of a Target cell-Biologics-Effector cell (TBE) complex-based cell killing model to characterize target cell depletion by T cell redirecting bispecific agents

Jiang

Chen

Carpenter

et al. 2018

mAbs

View full text Add to dashboard Cite

show abstract

“…There is a complex relationship between the size of CARs, the position of the epitope in their ligands and induction of killing 39 . Some observations are consistent with the KS model in that interactions that lead to intermembrane distances close enough to exclude CD45 are optimal for killing by CAR expressing CD8+ T cells 40 . Many solid tumors overexpress antigens that are also expressed at lower levels on normal tissue cells 38 .…”

Section: Discussionsupporting

confidence: 72%

Full control of ligand positioning reveals spatial thresholds for T cell receptor triggering

et al. 2018

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Elucidating the rules for receptor triggering in cell-cell and cell-matrix contacts requires precise control of ligand positioning in three dimensions. Here, we use the T cell receptor (TCR) as a model and subject T cells to different geometric arrangements of ligands, using a nanofabricated single-molecule array platform. This is comprised of monovalent TCR ligands anchored to lithographically patterned nanoparticle clusters surrounded by mobile adhesion molecules on a supported lipid bilayer (SLB). The TCR ligand could be co-planar with the SLB (2D), excluding the CD45 transmembrane tyrosine phosphatase, or elevated by 10 nm on solid nanopedestals (3D), allowing closer access of CD45 to engaged TCR. The two configurations resulted in different T cell responses, depending on the lateral spacing between the ligands. These results identify the important contributions of lateral and axial components of ligand positioning and create a more complete foundation for receptor engineering for immunotherapy.

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“…Studies with hexamerization-enhanced variants of EGFR antibodies have demonstrated that matuzumab is particularly efficient in triggering CDC, which may be related to its particular orientation of binding (37). Recently reported results have demonstrated that characteristics of target antigen epitopessuch as their distance to the tumor cell membrane-differently affect the efficacy of particular effector mechanisms of therapeutic antibodies (40,41).…”

Section: Discussionmentioning

confidence: 99%

Immune Effector Functions of Human IgG2 Antibodies against EGFR

Rösner

Kahle

Montenegro

et al. 2019

Molecular Cancer Therapeutics

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Three FDA-approved epidermal growth factor receptor (EGFR) antibodies (cetuximab, panitumumab, necitumumab) are clinically available to treat patients with different types of cancers. Interestingly, panitumumab is of human IgG2 isotype, which is often considered to have limited immune effector functions. Unexpectedly, our studies unraveled that human IgG2 antibodies against EGFR mediated effective CDC when combined with another noncrossblocking EGFR antibody. This second antibody could be of human IgG1 or IgG2 isotype. Furthermore, EGFR antibodies of human IgG2 isotype were highly potent in recruiting myeloid effector cells such as M1 macrophages and PMN for tumor cell killing by ADCC. Tumor cell killing by PMN was more effective with IgG2 than with IgG1 antibodies if tumor cells expressed lower levels of EGFR. Additionally, lower expression levels of the "don't eat me" molecule CD47 on tumor cells enabled ADCC also by M2 macrophages, and improved PMN and macrophage-mediated ADCC. A TCGA enquiry revealed broadly varying CD47 expression levels across different solid tumor types. Together, these results demonstrate that human IgG2 antibodies against EGFR can promote significant Fc-mediated effector functions, which may contribute to their clinical efficacy. The future challenge will be to identify clinical situations in which myeloid effector cells can optimally contribute to antibody efficacy.

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Membrane-Proximal Epitope Facilitates Efficient T Cell Synapse Formation by Anti-FcRH5/CD3 and Is a Requirement for Myeloma Cell Killing

Cited by 225 publications

References 23 publications

Development of a Target cell-Biologics-Effector cell (TBE) complex-based cell killing model to characterize target cell depletion by T cell redirecting bispecific agents

Development of a Target cell-Biologics-Effector cell (TBE) complex-based cell killing model to characterize target cell depletion by T cell redirecting bispecific agents

Full control of ligand positioning reveals spatial thresholds for T cell receptor triggering

Immune Effector Functions of Human IgG2 Antibodies against EGFR

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