Addressing Safety Liabilities of TfR Bispecific Antibodies That Cross the Blood-Brain Barrier

Jessica A. Couch; Y. Joy Yu; Yin Zhang; Jacqueline M. Tarrant; Reina N. Fuji; William J. Meilandt; Hilda Solanoy; Raymond K. Tong; Kwame Hoyte; Wilman Luk; Yanmei Lu; Kapil Gadkar; Saileta Prabhu; Benjamin A. Ordonia; Quyen Nguyen; Yuwen Lin; Zhonghua Lin; Mercedesz Balazs; Kimberly Scearce-Levie; James A. Ernst; Mark S. Dennis; Ryan J. Watts

doi:10.1126/scitranslmed.3005338

Research ArticleTherapeutic Antibodies

Addressing Safety Liabilities of TfR Bispecific Antibodies That Cross the Blood-Brain Barrier

Jessica A. Couch¹,*,
Y. Joy Yu²,*,
Yin Zhang³,
Jacqueline M. Tarrant¹,
Reina N. Fuji¹,
William J. Meilandt²,
Hilda Solanoy²,
Raymond K. Tong⁴,
Kwame Hoyte⁵,
Wilman Luk⁵,
Yanmei Lu⁵,
Kapil Gadkar¹,
Saileta Prabhu¹,
Benjamin A. Ordonia¹,
Quyen Nguyen¹,
Yuwen Lin¹,
Zhonghua Lin⁶,
Mercedesz Balazs⁶,
Kimberly Scearce-Levie²,
James A. Ernst⁴,
Mark S. Dennis³,† and
Ryan J. Watts²,†

¹Development Sciences, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
²Neurodegeneration Labs, Department of Neuroscience, Genentech Inc., South San Francisco, CA 94080, USA.
³Antibody Engineering, Genentech Inc., South San Francisco, CA 94080, USA.
⁴Protein Chemistry, Genentech Inc., South San Francisco, CA 94080, USA.
⁵Biochemical and Cellular Pharmacology, Genentech Inc., South San Francisco, CA 94080, USA.
⁶Translational Immunology, Genentech Inc., South San Francisco, CA 94080, USA.

↵†Corresponding author. E-mail: rwatts{at}gene.com (R.J.W.); msd{at}gene.com (M.S.D.)

↵* These authors contributed equally to this work.

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Science Translational Medicine 01 May 2013:
Vol. 5, Issue 183, pp. 183ra57
DOI: 10.1126/scitranslmed.3005338

Jessica A. Couch

1Development Sciences, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.

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Y. Joy Yu

2Neurodegeneration Labs, Department of Neuroscience, Genentech Inc., South San Francisco, CA 94080, USA.

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Yin Zhang

3Antibody Engineering, Genentech Inc., South San Francisco, CA 94080, USA.

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Jacqueline M. Tarrant

1Development Sciences, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.

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Reina N. Fuji

1Development Sciences, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.

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William J. Meilandt

2Neurodegeneration Labs, Department of Neuroscience, Genentech Inc., South San Francisco, CA 94080, USA.

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Hilda Solanoy

2Neurodegeneration Labs, Department of Neuroscience, Genentech Inc., South San Francisco, CA 94080, USA.

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Raymond K. Tong

4Protein Chemistry, Genentech Inc., South San Francisco, CA 94080, USA.

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Kwame Hoyte

5Biochemical and Cellular Pharmacology, Genentech Inc., South San Francisco, CA 94080, USA.

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Wilman Luk

5Biochemical and Cellular Pharmacology, Genentech Inc., South San Francisco, CA 94080, USA.

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Yanmei Lu

5Biochemical and Cellular Pharmacology, Genentech Inc., South San Francisco, CA 94080, USA.

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Kapil Gadkar

1Development Sciences, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.

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Saileta Prabhu

1Development Sciences, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.

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Benjamin A. Ordonia

1Development Sciences, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.

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Quyen Nguyen

1Development Sciences, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.

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Yuwen Lin

1Development Sciences, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.

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Zhonghua Lin

6Translational Immunology, Genentech Inc., South San Francisco, CA 94080, USA.

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Mercedesz Balazs

6Translational Immunology, Genentech Inc., South San Francisco, CA 94080, USA.

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Kimberly Scearce-Levie

2Neurodegeneration Labs, Department of Neuroscience, Genentech Inc., South San Francisco, CA 94080, USA.

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James A. Ernst

4Protein Chemistry, Genentech Inc., South San Francisco, CA 94080, USA.

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Mark S. Dennis

3Antibody Engineering, Genentech Inc., South San Francisco, CA 94080, USA.

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For correspondence: rwatts@gene.com msd@gene.com

Ryan J. Watts

2Neurodegeneration Labs, Department of Neuroscience, Genentech Inc., South San Francisco, CA 94080, USA.

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For correspondence: rwatts@gene.com msd@gene.com

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The safety of therapeutic bispecific antibodies that use TfR for delivery to the brain can be improved by reducing affinity for TfR and eliminating antibody effector function.

Addressing Safety Liabilities of TfR Bispecific Antibodies That Cross the Blood-Brain Barrier

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