Data from A Multispecific Anti-CD40 DARPin Construct Induces Tumor-Selective CD40 Activation and Tumor Regression Article Swipe
Nicolò Rigamonti
,
Niina Veitonmäki
,
Clara Domke
,
Sophie Barsin
,
Sarah Jetzer
,
Omar Abdelmotaleb
,
Ralph Bessey
,
Tamara Lekishvili
,
Francesca Malvezzi
,
Mariam Gachechiladze
,
Martin Béhé
,
Victor Levitsky
,
Pamela A. Trail
·
YOU?
·
· 2023
· Open Access
·
· DOI: https://doi.org/10.1158/2326-6066.c.6550722.v1
YOU?
·
· 2023
· Open Access
·
· DOI: https://doi.org/10.1158/2326-6066.c.6550722.v1
The CD40 receptor is an attractive target for cancer immunotherapy. Although a modest pharmacodynamic effect is seen in patients following administration of CD40-targeting monoclonal antibodies (mAb), the doses that could be safely administered do not result in a meaningful clinical response, most likely due to the limited therapeutic window associated with systemic CD40 activation. To overcome this issue, we developed a multispecific DARPin construct, α-FAPxCD40, which has conditional activity at the site of disease. α-FAPxCD40 activation of CD40 depends on binding to fibroblast activation protein (FAP), a cell-surface protease overexpressed in the stroma of solid tumors. In vitro studies demonstrated that α-FAPxCD40 potently activates human antigen-presenting cells in the presence, but not in the absence, of FAP-positive cells. After intravenous injection, a murine surrogate construct (α-mFAPxCD40) accumulated in FAP-positive tumors, elicited rejection of 88% of these tumors, and induced memory antitumor immunity. Importantly, in contrast to the mouse anti-CD40 tested in parallel, the in vivo antitumor activity of α-mFAPxCD40 was associated neither with elevated blood cytokines nor with hepatotoxicity, both of which contribute to the clinical dose-limiting toxicities of several CD40 mAb. This study demonstrates that α-(m)FAPxCD40 engages CD40 in an FAP-restricted manner, leading to tumor eradication without signs of peripheral toxicity. This distinct preclinical profile suggests that a favorable therapeutic index may be achieved in humans. It further supports the development of α-FAPxCD40, currently tested in a first-in-human clinical study in patients with solid tumors (NCT05098405).
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Metadata
- Type
- preprint
- Language
- en
- Landing Page
- http://doi.org/10.1158/2326-6066.c.6550722.v1
- OA Status
- gold
- Related Works
- 10
- OpenAlex ID
- https://openalex.org/W4362547221
All OpenAlex metadata
Raw OpenAlex JSON
- OpenAlex ID
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https://openalex.org/W4362547221Canonical identifier for this work in OpenAlex
- DOI
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https://doi.org/10.1158/2326-6066.c.6550722.v1Digital Object Identifier
- Title
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Data from A Multispecific Anti-CD40 DARPin Construct Induces Tumor-Selective CD40 Activation and Tumor RegressionWork title
- Type
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preprintOpenAlex work type
- Language
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enPrimary language
- Publication year
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2023Year of publication
- Publication date
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2023-04-04Full publication date if available
- Authors
-
Nicolò Rigamonti, Niina Veitonmäki, Clara Domke, Sophie Barsin, Sarah Jetzer, Omar Abdelmotaleb, Ralph Bessey, Tamara Lekishvili, Francesca Malvezzi, Mariam Gachechiladze, Martin Béhé, Victor Levitsky, Pamela A. TrailList of authors in order
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https://doi.org/10.1158/2326-6066.c.6550722.v1Publisher landing page
- Open access
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YesWhether a free full text is available
- OA status
-
goldOpen access status per OpenAlex
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https://doi.org/10.1158/2326-6066.c.6550722.v1Direct OA link when available
- Concepts
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CD40, Cancer research, Medicine, In vivo, Antibody, Pharmacology, Monoclonal antibody, Immunotherapy, Immunology, In vitro, Immune system, Biology, Cytotoxic T cell, Biochemistry, BiotechnologyTop concepts (fields/topics) attached by OpenAlex
- Cited by
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0Total citation count in OpenAlex
- Related works (count)
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10Other works algorithmically related by OpenAlex
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| abstract_inverted_index.tumors. | 95 |
| abstract_inverted_index.without | 197 |
| abstract_inverted_index.Although | 10 |
| abstract_inverted_index.absence, | 114 |
| abstract_inverted_index.achieved | 214 |
| abstract_inverted_index.activity | 68, 156 |
| abstract_inverted_index.clinical | 39, 175, 229 |
| abstract_inverted_index.contrast | 144 |
| abstract_inverted_index.disease. | 73 |
| abstract_inverted_index.distinct | 203 |
| abstract_inverted_index.elevated | 163 |
| abstract_inverted_index.elicited | 130 |
| abstract_inverted_index.overcome | 55 |
| abstract_inverted_index.patients | 18, 232 |
| abstract_inverted_index.potently | 102 |
| abstract_inverted_index.protease | 88 |
| abstract_inverted_index.receptor | 2 |
| abstract_inverted_index.suggests | 206 |
| abstract_inverted_index.supports | 219 |
| abstract_inverted_index.systemic | 51 |
| abstract_inverted_index.activates | 103 |
| abstract_inverted_index.anti-CD40 | 148 |
| abstract_inverted_index.antitumor | 140, 155 |
| abstract_inverted_index.construct | 124 |
| abstract_inverted_index.currently | 224 |
| abstract_inverted_index.cytokines | 165 |
| abstract_inverted_index.developed | 59 |
| abstract_inverted_index.favorable | 209 |
| abstract_inverted_index.following | 19 |
| abstract_inverted_index.immunity. | 141 |
| abstract_inverted_index.parallel, | 151 |
| abstract_inverted_index.presence, | 109 |
| abstract_inverted_index.rejection | 131 |
| abstract_inverted_index.response, | 40 |
| abstract_inverted_index.surrogate | 123 |
| abstract_inverted_index.toxicity. | 201 |
| abstract_inverted_index.activation | 75, 83 |
| abstract_inverted_index.antibodies | 24 |
| abstract_inverted_index.associated | 49, 160 |
| abstract_inverted_index.attractive | 5 |
| abstract_inverted_index.construct, | 63 |
| abstract_inverted_index.contribute | 172 |
| abstract_inverted_index.fibroblast | 82 |
| abstract_inverted_index.injection, | 120 |
| abstract_inverted_index.meaningful | 38 |
| abstract_inverted_index.monoclonal | 23 |
| abstract_inverted_index.peripheral | 200 |
| abstract_inverted_index.toxicities | 177 |
| abstract_inverted_index.<i>In | 96 |
| abstract_inverted_index.<i>in | 153 |
| abstract_inverted_index.accumulated | 126 |
| abstract_inverted_index.activation. | 53 |
| abstract_inverted_index.conditional | 67 |
| abstract_inverted_index.development | 221 |
| abstract_inverted_index.eradication | 196 |
| abstract_inverted_index.intravenous | 119 |
| abstract_inverted_index.preclinical | 204 |
| abstract_inverted_index.therapeutic | 47, 210 |
| abstract_inverted_index.α-FAPxCD40 | 74, 101 |
| abstract_inverted_index.FAP-positive | 116, 128 |
| abstract_inverted_index.Importantly, | 142 |
| abstract_inverted_index.administered | 32 |
| abstract_inverted_index.cell-surface | 87 |
| abstract_inverted_index.demonstrated | 99 |
| abstract_inverted_index.demonstrates | 184 |
| abstract_inverted_index.α-FAPxCD40, | 64, 223 |
| abstract_inverted_index.α-mFAPxCD40 | 158 |
| abstract_inverted_index.dose-limiting | 176 |
| abstract_inverted_index.multispecific | 61 |
| abstract_inverted_index.overexpressed | 89 |
| abstract_inverted_index.(α-mFAPxCD40) | 125 |
| abstract_inverted_index.CD40-targeting | 22 |
| abstract_inverted_index.FAP-restricted | 191 |
| abstract_inverted_index.administration | 20 |
| abstract_inverted_index.first-in-human | 228 |
| abstract_inverted_index.immunotherapy. | 9 |
| abstract_inverted_index.vivo</i> | 154 |
| abstract_inverted_index.α-(m)FAPxCD40 | 186 |
| abstract_inverted_index.hepatotoxicity, | 168 |
| abstract_inverted_index.pharmacodynamic | 13 |
| abstract_inverted_index.vitro</i> | 97 |
| abstract_inverted_index.antigen-presenting | 105 |
| abstract_inverted_index.<div>Abstract<p>The | 0 |
| abstract_inverted_index.(NCT05098405).</p></div> | 236 |
| cited_by_percentile_year | |
| countries_distinct_count | 0 |
| institutions_distinct_count | 13 |
| sustainable_development_goals[0].id | https://metadata.un.org/sdg/3 |
| sustainable_development_goals[0].score | 0.6899999976158142 |
| sustainable_development_goals[0].display_name | Good health and well-being |
| citation_normalized_percentile.value | 0.28296091 |
| citation_normalized_percentile.is_in_top_1_percent | False |
| citation_normalized_percentile.is_in_top_10_percent | False |