Impact of tissue penetration and albumin binding on design of T cell targeted bispecific agents
Bispecific agents are a rapidly growing class of cancer therapeutics, and immune targeted bispecific agents have the potential to expand functionality well beyond monoclonal antibody agents. Humabodies⁎⁎ Humabody® is a registered trademark of Crescendo Biologics Ltd. are fully human single domain an...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2024-02-01
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| Series: | Neoplasia: An International Journal for Oncology Research |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S1476558623000854 |
| _version_ | 1797334829984907264 |
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| author | Anna Kopp Hyeyoung Kwon Colette Johnston Steven Vance James Legg Laurie Galson-Holt Greg M. Thurber |
| author_facet | Anna Kopp Hyeyoung Kwon Colette Johnston Steven Vance James Legg Laurie Galson-Holt Greg M. Thurber |
| author_sort | Anna Kopp |
| collection | DOAJ |
| description | Bispecific agents are a rapidly growing class of cancer therapeutics, and immune targeted bispecific agents have the potential to expand functionality well beyond monoclonal antibody agents. Humabodies⁎⁎ Humabody® is a registered trademark of Crescendo Biologics Ltd. are fully human single domain antibodies that can be linked in a modular fashion to form multispecific therapeutics. However, the effect of heterogeneous delivery on the efficacy of crosslinking bispecific agents is currently unclear. In this work, we utilize a PSMA-CD137 Humabody with an albumin binding half-life extension (HLE) domain to determine the impact of tissue penetration on T cell activating bispecific agents. Using heterotypic spheroids, we demonstrate that increased tissue penetration results in higher T cell activation at sub-saturating concentrations. Next, we tested the effect of two different albumin binding moieties on tissue distribution using albumin-specific HLE domains with varying affinities for albumin and a non-specific lipophilic dye. The results show that a specific binding mechanism to albumin does not influence tissue penetration, but a non-specific mechanism reduced both spheroid uptake and distribution in the presence of albumin. These results highlight the potential importance of tissue penetration on bispecific agent efficacy and describe how the design parameters including albumin-binding domains can be selected to maximize the efficacy of bispecific agents. |
| first_indexed | 2024-03-08T08:26:55Z |
| format | Article |
| id | doaj.art-e10bbca475e14f86ac0602ed0855f6fb |
| institution | Directory Open Access Journal |
| issn | 1476-5586 |
| language | English |
| last_indexed | 2024-03-08T08:26:55Z |
| publishDate | 2024-02-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neoplasia: An International Journal for Oncology Research |
| spelling | doaj.art-e10bbca475e14f86ac0602ed0855f6fb2024-02-02T04:38:43ZengElsevierNeoplasia: An International Journal for Oncology Research1476-55862024-02-0148100962Impact of tissue penetration and albumin binding on design of T cell targeted bispecific agentsAnna Kopp0Hyeyoung Kwon1Colette Johnston2Steven Vance3James Legg4Laurie Galson-Holt5Greg M. Thurber6Department of Chemical Engineering, University of Michigan, Ann Arbor, MI 48109, United StatesDepartment of Chemical Engineering, University of Michigan, Ann Arbor, MI 48109, United StatesCrescendo Biologics, Cambridge, United KingdomCrescendo Biologics, Cambridge, United KingdomCrescendo Biologics, Cambridge, United KingdomCrescendo Biologics, Cambridge, United KingdomDepartment of Chemical Engineering, University of Michigan, Ann Arbor, MI 48109, United States; Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI 48109, United States; Biointerfaces Institute, University of Michigan, Ann Arbor, MI 48109, United States; Rogel Cancer Center, University of Michigan, Ann Arbor, MI 48109, United States; Corresponding author.Bispecific agents are a rapidly growing class of cancer therapeutics, and immune targeted bispecific agents have the potential to expand functionality well beyond monoclonal antibody agents. Humabodies⁎⁎ Humabody® is a registered trademark of Crescendo Biologics Ltd. are fully human single domain antibodies that can be linked in a modular fashion to form multispecific therapeutics. However, the effect of heterogeneous delivery on the efficacy of crosslinking bispecific agents is currently unclear. In this work, we utilize a PSMA-CD137 Humabody with an albumin binding half-life extension (HLE) domain to determine the impact of tissue penetration on T cell activating bispecific agents. Using heterotypic spheroids, we demonstrate that increased tissue penetration results in higher T cell activation at sub-saturating concentrations. Next, we tested the effect of two different albumin binding moieties on tissue distribution using albumin-specific HLE domains with varying affinities for albumin and a non-specific lipophilic dye. The results show that a specific binding mechanism to albumin does not influence tissue penetration, but a non-specific mechanism reduced both spheroid uptake and distribution in the presence of albumin. These results highlight the potential importance of tissue penetration on bispecific agent efficacy and describe how the design parameters including albumin-binding domains can be selected to maximize the efficacy of bispecific agents.http://www.sciencedirect.com/science/article/pii/S1476558623000854Bispecific antibodiesTumoral distributionT-cell activating agentsSingle domain antibodiesHeterotypic spheroids |
| spellingShingle | Anna Kopp Hyeyoung Kwon Colette Johnston Steven Vance James Legg Laurie Galson-Holt Greg M. Thurber Impact of tissue penetration and albumin binding on design of T cell targeted bispecific agents Neoplasia: An International Journal for Oncology Research Bispecific antibodies Tumoral distribution T-cell activating agents Single domain antibodies Heterotypic spheroids |
| title | Impact of tissue penetration and albumin binding on design of T cell targeted bispecific agents |
| title_full | Impact of tissue penetration and albumin binding on design of T cell targeted bispecific agents |
| title_fullStr | Impact of tissue penetration and albumin binding on design of T cell targeted bispecific agents |
| title_full_unstemmed | Impact of tissue penetration and albumin binding on design of T cell targeted bispecific agents |
| title_short | Impact of tissue penetration and albumin binding on design of T cell targeted bispecific agents |
| title_sort | impact of tissue penetration and albumin binding on design of t cell targeted bispecific agents |
| topic | Bispecific antibodies Tumoral distribution T-cell activating agents Single domain antibodies Heterotypic spheroids |
| url | http://www.sciencedirect.com/science/article/pii/S1476558623000854 |
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