Generation of T-cell-redirecting bispecific antibodies with differentiated profiles of cytokine release and biodistribution by CD3 affinity tuning
Abstract T-cell-redirecting bispecific antibodies have emerged as a new class of therapeutic agents designed to simultaneously bind to T cells via CD3 and to tumor cells via tumor-cell-specific antigens (TSA), inducing T-cell-mediated killing of tumor cells. The promising preclinical and clinical ef...
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2021-07-01
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Online Access: | https://doi.org/10.1038/s41598-021-93842-0 |
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doaj-13db8e3e17e043ffbbadbbb6bb988d632021-07-18T11:25:48ZengNature Publishing GroupScientific Reports2045-23222021-07-0111111710.1038/s41598-021-93842-0Generation of T-cell-redirecting bispecific antibodies with differentiated profiles of cytokine release and biodistribution by CD3 affinity tuningLauric Haber0Kara Olson1Marcus P. Kelly2Alison Crawford3David J. DiLillo4Richard Tavaré5Erica Ullman6Shu Mao7Lauren Canova8Olga Sineshchekova9Jennifer Finney10Arpita Pawashe11Supriya Patel12Ryan McKay13Sahar Rizvi14Ermelinda Damko15Danica Chiu16Kristin Vazzana17Priyanka Ram18Katja Mohrs19Amanda D’Orvilliers20Jenny Xiao21Sosina Makonnen22Carlos Hickey23Cody Arnold24Jason Giurleo25Ya Ping Chen26Courtney Thwaites27Drew Dudgeon28Kevin Bray29Ashique Rafique30Tammy Huang31Frank Delfino32Aynur Hermann33Jessica R. Kirshner34Marc W. Retter35Robert Babb36Douglas MacDonald37Gang Chen38William C. Olson39Gavin Thurston40Samuel Davis41John C. Lin42Eric Smith43Regeneron Pharmaceuticals, IncRegeneron Pharmaceuticals, IncRegeneron Pharmaceuticals, IncRegeneron Pharmaceuticals, IncRegeneron Pharmaceuticals, IncRegeneron Pharmaceuticals, IncRegeneron Pharmaceuticals, IncRegeneron Pharmaceuticals, IncRegeneron Pharmaceuticals, IncRegeneron Pharmaceuticals, IncRegeneron Pharmaceuticals, IncRegeneron Pharmaceuticals, IncRegeneron Pharmaceuticals, IncRegeneron Pharmaceuticals, IncRegeneron Pharmaceuticals, IncRegeneron Pharmaceuticals, IncAstraZenecaRegeneron Pharmaceuticals, IncRegeneron Pharmaceuticals, IncRegeneron Pharmaceuticals, IncRegeneron Pharmaceuticals, IncRegeneron Pharmaceuticals, IncRegeneron Pharmaceuticals, IncRegeneron Pharmaceuticals, IncRegeneron Pharmaceuticals, IncRegeneron Pharmaceuticals, IncRegeneron Pharmaceuticals, IncLonzaRegeneron Pharmaceuticals, IncRegeneron Pharmaceuticals, IncRegeneron Pharmaceuticals, IncRegeneron Pharmaceuticals, IncRegeneron Pharmaceuticals, IncRegeneron Pharmaceuticals, IncRegeneron Pharmaceuticals, IncRegeneron Pharmaceuticals, IncRegeneron Pharmaceuticals, IncRegeneron Pharmaceuticals, IncRegeneron Pharmaceuticals, IncRegeneron Pharmaceuticals, IncRegeneron Pharmaceuticals, IncRegeneron Pharmaceuticals, IncRegeneron Pharmaceuticals, IncRegeneron Pharmaceuticals, IncAbstract T-cell-redirecting bispecific antibodies have emerged as a new class of therapeutic agents designed to simultaneously bind to T cells via CD3 and to tumor cells via tumor-cell-specific antigens (TSA), inducing T-cell-mediated killing of tumor cells. The promising preclinical and clinical efficacy of TSAxCD3 antibodies is often accompanied by toxicities such as cytokine release syndrome due to T-cell activation. How the efficacy and toxicity profile of the TSAxCD3 bispecific antibodies depends on the binding affinity to CD3 remains unclear. Here, we evaluate bispecific antibodies that were engineered to have a range of CD3 affinities, while retaining the same binding affinity for the selected tumor antigen. These agents were tested for their ability to kill tumor cells in vitro, and their biodistribution, serum half-life, and anti-tumor activity in vivo. Remarkably, by altering the binding affinity for CD3 alone, we can generate bispecific antibodies that maintain potent killing of TSA + tumor cells but display differential patterns of cytokine release, pharmacokinetics, and biodistribution. Therefore, tuning CD3 affinity is a promising method to improve the therapeutic index of T-cell-engaging bispecific antibodies.https://doi.org/10.1038/s41598-021-93842-0 |
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DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Lauric Haber Kara Olson Marcus P. Kelly Alison Crawford David J. DiLillo Richard Tavaré Erica Ullman Shu Mao Lauren Canova Olga Sineshchekova Jennifer Finney Arpita Pawashe Supriya Patel Ryan McKay Sahar Rizvi Ermelinda Damko Danica Chiu Kristin Vazzana Priyanka Ram Katja Mohrs Amanda D’Orvilliers Jenny Xiao Sosina Makonnen Carlos Hickey Cody Arnold Jason Giurleo Ya Ping Chen Courtney Thwaites Drew Dudgeon Kevin Bray Ashique Rafique Tammy Huang Frank Delfino Aynur Hermann Jessica R. Kirshner Marc W. Retter Robert Babb Douglas MacDonald Gang Chen William C. Olson Gavin Thurston Samuel Davis John C. Lin Eric Smith |
spellingShingle |
Lauric Haber Kara Olson Marcus P. Kelly Alison Crawford David J. DiLillo Richard Tavaré Erica Ullman Shu Mao Lauren Canova Olga Sineshchekova Jennifer Finney Arpita Pawashe Supriya Patel Ryan McKay Sahar Rizvi Ermelinda Damko Danica Chiu Kristin Vazzana Priyanka Ram Katja Mohrs Amanda D’Orvilliers Jenny Xiao Sosina Makonnen Carlos Hickey Cody Arnold Jason Giurleo Ya Ping Chen Courtney Thwaites Drew Dudgeon Kevin Bray Ashique Rafique Tammy Huang Frank Delfino Aynur Hermann Jessica R. Kirshner Marc W. Retter Robert Babb Douglas MacDonald Gang Chen William C. Olson Gavin Thurston Samuel Davis John C. Lin Eric Smith Generation of T-cell-redirecting bispecific antibodies with differentiated profiles of cytokine release and biodistribution by CD3 affinity tuning Scientific Reports |
author_facet |
Lauric Haber Kara Olson Marcus P. Kelly Alison Crawford David J. DiLillo Richard Tavaré Erica Ullman Shu Mao Lauren Canova Olga Sineshchekova Jennifer Finney Arpita Pawashe Supriya Patel Ryan McKay Sahar Rizvi Ermelinda Damko Danica Chiu Kristin Vazzana Priyanka Ram Katja Mohrs Amanda D’Orvilliers Jenny Xiao Sosina Makonnen Carlos Hickey Cody Arnold Jason Giurleo Ya Ping Chen Courtney Thwaites Drew Dudgeon Kevin Bray Ashique Rafique Tammy Huang Frank Delfino Aynur Hermann Jessica R. Kirshner Marc W. Retter Robert Babb Douglas MacDonald Gang Chen William C. Olson Gavin Thurston Samuel Davis John C. Lin Eric Smith |
author_sort |
Lauric Haber |
title |
Generation of T-cell-redirecting bispecific antibodies with differentiated profiles of cytokine release and biodistribution by CD3 affinity tuning |
title_short |
Generation of T-cell-redirecting bispecific antibodies with differentiated profiles of cytokine release and biodistribution by CD3 affinity tuning |
title_full |
Generation of T-cell-redirecting bispecific antibodies with differentiated profiles of cytokine release and biodistribution by CD3 affinity tuning |
title_fullStr |
Generation of T-cell-redirecting bispecific antibodies with differentiated profiles of cytokine release and biodistribution by CD3 affinity tuning |
title_full_unstemmed |
Generation of T-cell-redirecting bispecific antibodies with differentiated profiles of cytokine release and biodistribution by CD3 affinity tuning |
title_sort |
generation of t-cell-redirecting bispecific antibodies with differentiated profiles of cytokine release and biodistribution by cd3 affinity tuning |
publisher |
Nature Publishing Group |
series |
Scientific Reports |
issn |
2045-2322 |
publishDate |
2021-07-01 |
description |
Abstract T-cell-redirecting bispecific antibodies have emerged as a new class of therapeutic agents designed to simultaneously bind to T cells via CD3 and to tumor cells via tumor-cell-specific antigens (TSA), inducing T-cell-mediated killing of tumor cells. The promising preclinical and clinical efficacy of TSAxCD3 antibodies is often accompanied by toxicities such as cytokine release syndrome due to T-cell activation. How the efficacy and toxicity profile of the TSAxCD3 bispecific antibodies depends on the binding affinity to CD3 remains unclear. Here, we evaluate bispecific antibodies that were engineered to have a range of CD3 affinities, while retaining the same binding affinity for the selected tumor antigen. These agents were tested for their ability to kill tumor cells in vitro, and their biodistribution, serum half-life, and anti-tumor activity in vivo. Remarkably, by altering the binding affinity for CD3 alone, we can generate bispecific antibodies that maintain potent killing of TSA + tumor cells but display differential patterns of cytokine release, pharmacokinetics, and biodistribution. Therefore, tuning CD3 affinity is a promising method to improve the therapeutic index of T-cell-engaging bispecific antibodies. |
url |
https://doi.org/10.1038/s41598-021-93842-0 |
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