Fcγ-receptor–mediated trogocytosis impacts mAb-based therapies: historical precedence and recent developments

Taylor, Ronald P.; Lindorfer, Margaret A.

doi:10.1182/blood-2014-10-569244

Cited by 132 publications

(124 citation statements)

References 72 publications

Supporting

Mentioning

118

Contrasting

Order By: Relevance

“…Knowledge gained from the KEL system, including that of anti-KEL sera leading to antigen modulation in the absence of complete RBC clearance, may inform other systems in which antibody prevention is desirable. 4,5 and Jeanne E. Hendrickson…”

Section: Letters To the Editormentioning

confidence: 99%

Anti-KEL sera prevents alloimmunization to transfused KEL RBCs in a murine model

et al. 2015

View full text Add to dashboard Cite

Section: Letters To the Editormentioning

confidence: 99%

Anti-KEL sera prevents alloimmunization to transfused KEL RBCs in a murine model

et al. 2015

View full text Add to dashboard Cite

“…Taylor and colleagues proposed that the shaving process occurred when effector cell populations become saturated and exhausted (reviewed in [45]). Shaving is proposed to leave the cells viable but refractory to clearance by subsequent effector functions as they are no longer coated with mAb.…”

Section: Antigenic Modulation: Antibody Shavingmentioning

confidence: 99%

“…Alternatively, in order to overcome the detrimental impact of antigen loss through shaving Taylor and colleagues have proposed that repeated low dose antibody administration, sufficient to clear cells but not, they suggest to saturate the effector populations, will enhance responses in CLL [55] and potentially to other direct targeting mAb [45].…”

Section: Antigenic Modulation: Antibody Shavingmentioning

confidence: 99%

“…Taylor and colleagues in [45] themselves concede that in contrast to their own pilot and phase I/II trials [56,57], "the results of a dose escalation trial for CLL indicated a higher level of efficacy for single agent rituximab at (higher) weekly doses of 2250 mg/m 2 " [58]. Further, the recent randomised Phase II NCRI Attenuated dose Rituximab with ChemoTherapy In CLL (ARCTIC) trial of low dose rituximab in previously untreated CLL closed the low rituximab arm early as it was inferior to standard FCR [59].…”

Section: Antigenic Modulation: Antibody Shavingmentioning

confidence: 99%

See 1 more Smart Citation

Antibody modulation: Limiting the efficacy of therapeutic antibodies

Vaughan

Cragg

Beers

2015

Pharmacological Research

View full text Add to dashboard Cite

Monoclonal antibodies (mAb) have revolutionised the way in which we treat disease.From cancer to autoimmunity, antibody therapy has been responsible for some of the most impressive clinical responses observed in the last 2 decades. A key component of this success has been their generally low levels of toxicity, and unique mechanisms of action. These two facets have allowed them to a) be integrated rapidly into clinical practice in combination with conventional radio-and chemotherapies and b) to avoid the resistance mechanisms typically observed with classical small molecule drugs, such as upregulation of drug efflux transporters, dysregulation of apoptosis and mutations in key target enzymes/pathways.Although success with mAb therapies has been impressive, they are also subject to their own resistance mechanisms. In this perspective we discuss the various ways in which mAb therapeutics can be inhibited, concentrating mainly on the ways in which they can be removed from the target cell surface -a process called modulation. This can be achieved either in a cis-fashion on a single cell or in trans, precipitated by engagement with a second phagocytic cell. The evidence for each of these processes will be discussed, in addition to possible therapeutic strategies that might be employed to inhibit or reverse them.Abbreviations: Fc gamma receptor, FcR; monoclonal antibody, mAb

show abstract

“…FcgR-mediated trogocytosis has been demonstrated for several other mAbs and their cellular targets, 8 Conflict-of-interest disclosure: The author declares no competing financial interests. n…”

mentioning

confidence: 99%

Neutrophils: positive or negative?

Taylor

2017

Blood

Self Cite

View full text Add to dashboard Cite

shown in Figure 2C-F of Tout et al). A separate group recently reported metabolic tumor volume was associated with outcomes in DLBCL patients with bone marrow involvement. 9 The additional contribution made in this current report by Tout and colleagues is that high TMTV 0 , which correlates with less favorable outcomes in patients receiving the standard 375 mg/m 2 dose of rituximab, also correlates with relatively low rituximab exposures. This same group had previously linked rituximab pharmacokinetics, tumor burden, and outcomes in a mouse model of lymphoma, 10 but the current report is the first to provide a clinical data set demonstrating the link between all 3 of these variables.Importantly, standard dosing in DLBCL with rituximab has remained at 375 mg/m 2 since early in its clinical development. Tout and colleagues have also constructed a nomogram based on their data, which provides a rational scheme for increasing the rituximab dose in patients with high TMTV 0 to achieve rituximab exposures that have a better chance of prolonging the duration of response. Thus, this work provides strong rationale and even a path forward for considering personalized rituximab dosing based on individual TMTV 0 in patients with DLBCL. There are many other immunotherapies that have been approved or are in development, and these target CD20 plus a variety of other antigens. Given that the basic behavior of these therapies will be similar to rituximab (ie, highaffinity and high-specificity binding to a single cancer-associated antigen), we can expect that similar relationships between target expression, pharmacokinetic exposure of these antibodies, and outcomes from therapy may exist, thus indicating that personalized dosing strategies may be feasible in diseases where target expression and/or tumor burden can be quantified. A recent review by Ku, Chong, and Hawkes 3 nicely summarizes immunotherapies more recently approved or in development for B-cell malignancies, and they also point out that dosing regimens could be more optimally tuned for individuals. Although the proposed dosing nomogram for rituximab presented by Tout and colleagues must be further tested and validated, future personalized dosing regimen designs for other existing and new antibody therapies could benefit from the lessons learned with rituximab and the approaches taken by this group. Neutrophils: positive or negative?In this issue of Blood, Valgardsdottir et al demonstrate that human neutrophils do not kill chronic lymphocytic leukemia (CLL) B cells opsonized with the CD20 monoclonal antibody (mAb) rituximab (RTX) or obinutuzumab (OBZ); instead, the neutrophils remove both CD20 and bound mAbs from B cells by trogocytosis. 1 T he CD20 mAb RTX was approved 20 years ago for treatment of relapsed or refractory, low-grade or follicular, B-cell non-Hodgkin lymphoma, and since that time, several nextgeneration CD20 mAbs have been approved or are under development for a variety of B-cell-associated malignancies.2 Although therapies that include CD20 mAbs (usuall...

show abstract

Fcγ-receptor–mediated trogocytosis impacts mAb-based therapies: historical precedence and recent developments

Cited by 132 publications

References 72 publications

Anti-KEL sera prevents alloimmunization to transfused KEL RBCs in a murine model

Anti-KEL sera prevents alloimmunization to transfused KEL RBCs in a murine model

Antibody modulation: Limiting the efficacy of therapeutic antibodies

Neutrophils: positive or negative?

Contact Info

Product

Resources

About