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Relative Target Affinities of T-Cell–Dependent Bispecific Antibodies Determine Biodistribution in a Solid Tumor Mouse Model
Published version of a preprint
Abstract
Anti-HER2/CD3, a T-cell–dependent bispecific antibody (TDB) construct, induces T-cell–mediated cell death in cancer cells expressing HER2 by cross-linking tumor HER2 with CD3 on cytotoxic T cells, thereby creating a functional cytolytic synapse. TDB design is a very challenging process that requires consideration of multiple parameters. Although therapeutic antibody design strategy is commonly driven by striving for the highest attainable antigen-binding affinity, little is known about how the affinity of each TDB arm can affect the targeting ability of the other arm and the consequent distribution and efficacy. To our knowledge, no distribution studies have been published using preclinical models wherein the T-cell–targeting arm of the TDB is actively bound to T cells. We used a combined approach involving radiochemistry, invasive biodistribution, and noninvasive single-photon emission tomographic (SPECT) imaging to measure TDB distribution and catabolism in transgenic mice with human CD3ϵ expression on T cells. Using CD3 affinity variants, we assessed the impact of CD3 affinity on short-term pharmacokinetics, tissue distribution, and cellular uptake. Our experimental approach determined the relative effects of (i) CD3 targeting to normal tissues, (ii) HER2 targeting to HER2-expressing tumors, and (iii) relative HER2/CD3 affinity, all as critical drivers for TDB distribution. We observed a strong correlation between CD3 affinity and distribution to T-cell–rich tissues, with higher CD3 affinity reducing systemic exposure and shifting TDB distribution away from tumor to T-cell–containing tissues. These observations have important implications for clinical translation of bispecific antibodies for cancer immunotherapy. Mol Cancer Ther; 17(4); 776–85. ©2018 AACR.
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The relative HER2/CD3 affinity is a critical driver for TDB distribution and catabolism in transgenic mouse models.
“Mandikian et al. showed that the relative HER2/CD3 affinity is a critical driver for TDB distribution and catabolism in transgenic mouse models.”
From Tutorial on monoclonal antibody pharmacokinetics and its considerations in early development (2018) · cites this paper as [91]
There is a strong correlation between CD3 affinity and distribution to T-cell-rich tissues, with higher CD3 affinity reducing systemic exposure and shifting TDB distribution away from tumor to T cell-containing tissues.
“They also showed that there was a strong correlation between CD3 affinity and distribution to T‐cell‐rich tissues, with higher CD3 affinity reducing systemic exposure and shifting TDB distribution away from tumor to T cell‐containing tissues91”
From Tutorial on monoclonal antibody pharmacokinetics and its considerations in early development (2018) · cites this paper as [91]
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“S6C), indicating a balanced engagement of both targets, a key feature for the tumor biodistribution of BiTE antibodies (23).”
Background
Metadata
- Authors
- Mandikian, D., Takahashi, N., Lo, A. A., Li, J., Eastham-Anderson, J., Slaga, D., Ho, J., Hristopoulos, M., Clark, R., Totpal, K., Lin, K., Joseph, S. B., Dennis, M. S., Prabhu, S., Junttila, T. T., & Boswell, C. A.
- Affiliations
- 1Genentech, Inc., South San Francisco, California.
- Northwestern University (US)
- NGM Biopharmaceuticals (United States) (US)
- California Institute for Biomedical Research (US)
- Denali Therapeutics (United States) (US)
- ORCID
- Venue
- Molecular Cancer Therapeutics
- Published
- 2018-04-01
- Volume
- 17
- Issue
- 4
- Pages
- 776-785
- ISSN
- 1535-7163 (ISSN-L)
- 1538-8514
- OpenAlex
- W2783911823
- Cited by
- 155
- References
- 29
- Citations by year
- 2026: 11 · 2025: 16 · 2024: 25 · 2023: 21 · 2022: 17 · 2021: 26 · 2020: 19 · 2019: 11 · 2018: 7
- FWCI
- 10.87
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Molecular Cancer Therapeutics (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Genentech (Genentech, Inc.)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Monoclonal and Polyclonal Antibodies Research
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Radiopharmaceutical Chemistry and Applications
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Keywords
- HER2, tissue distribution, pharmacokinetics, T cell cytotoxicity, tumor targeting, SPECT imaging, antibody catabolism, cancer immunotherapy
- MeSH terms
- Animals, Antibody Affinity, Colonic Neoplasms, Disease Models, Animal, Female, Humans, Immunotherapy, Mice, Nude, Mice, Transgenic, T-Lymphocytes, Cytotoxic, Tissue Distribution, Tumor Cells, Cultured, CD3 Complex, Antibodies, Bispecific, Erb-b2 Receptor Tyrosine Kinases, Mice
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