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Research Article
Nicole Vincent Jordan
Novartis Institutes for Biomedical Research, Cambridge, MA
Corresponding Author
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High-grade serous ovarian cancers (HGSOC) represent the most common of the ovarian malignancies. Due to the frequency of late-stage diagnosis and high rates of recurrence following standard of care treatments, novel therapies are needed to promote durable responses. We investigated the anti-tumor activity of CD3 T cell-engaging bispecific antibodies (TCBs) directed against the PAX8 lineage-driven HGSOC tumor antigen LYPD1 and demonstrated that anti-LYPD1 TCBs induce T cell activation and promote in vivo tumor growth inhibition in LYPD1-expressing HGSOC. To selectively target LYPD1-expressing tumor cells with high expression while sparing cells with low expression, we coupled bivalent low-affinity anti-LYPD1 Fabs with the anti-CD3 SP34 scFv. In contrast to the monovalent anti-LYPD1 high-affinity TCB (VHP354), the bivalent low-affinity anti-LYPD1 TCB (QZC131) demonstrated antigen density-dependent selectivity and showed tolerability in cynomolgus monkeys at the maximum dose tested of 3 mpk. Collectively, these data demonstrate that bivalent TCBs directed against LYPD1 have compelling efficacy and safety profiles supportive of consideration for treatment of high-grade serous ovarian cancers.
Keywords
high-grade serous ovarian cancers, CD3 T cell-engaging, PAX8 lineage-driven, LYPD1
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Competing interest reported. The authors are employees of Novartis Institute of Biomedical Research and Novartis.
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Reviewer #2 agreed
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This preprint is under consideration at Scientific Reports. A preprint is a preliminary version of a manuscript that has not completed peer review at a journal. Research Square does not conduct peer review prior to posting preprints. The posting of a preprint on this server should not be interpreted as an endorsement of its validity or suitability for dissemination as established information or for guiding clinical practice.
Learn more about In Review
Research Article
Nicole Vincent Jordan
Novartis Institutes for Biomedical Research, Cambridge, MA
Corresponding Author
Badges
Prescreen
This manuscript passed our Prescreen assessment
Complete author information
Appropriate declaration statements
Potential risks to human health
Prescreen
Peer Review Timeline
CURRENT STATUS: Under Revision
Version 1
Posted 18 Mar, 2021
No community comments so far
Editorial decision: Major revision
On 20 Apr, 2021
Review #2 received
Received 08 Apr, 2021
Review #3 received
Received 08 Apr, 2021
Review #4 received
Received 08 Apr, 2021
Review #1 received
Received 08 Apr, 2021
Reviewer #3 agreed
On 24 Mar, 2021
Reviewer #4 agreed
On 24 Mar, 2021
Reviewer #5 agreed
On 24 Mar, 2021
Reviewer #30 agreed
On 21 Mar, 2021
Reviewer #1 agreed
On 21 Mar, 2021
Reviewer #12 agreed
On 21 Mar, 2021
Reviewer #24 agreed
On 21 Mar, 2021
Reviewer #26 agreed
On 21 Mar, 2021
Reviewer #28 agreed
On 21 Mar, 2021
Reviewer #31 agreed
On 21 Mar, 2021
Reviewer #32 agreed
On 21 Mar, 2021
Reviewer #29 agreed
On 21 Mar, 2021
Reviewer #27 agreed
On 21 Mar, 2021
Reviewer #13 agreed
On 21 Mar, 2021
Reviewer #2 agreed
On 21 Mar, 2021
Reviewer #23 agreed
On 21 Mar, 2021
Reviewers invited
Invitations sent on 17 Mar, 2021
Editor assigned
On 17 Mar, 2021
Editor invited
On 17 Mar, 2021
Submission checks complete
On 17 Mar, 2021
First submitted
On 03 Mar, 2021
Metrics
Comments: 0
PDF Downloads: ...
HTML Views: ...
License:
This work is licensed under a CC BY 4.0 License. Read Full License
High-grade serous ovarian cancers (HGSOC) represent the most common of the ovarian malignancies. Due to the frequency of late-stage diagnosis and high rates of recurrence following standard of care treatments, novel therapies are needed to promote durable responses. We investigated the anti-tumor activity of CD3 T cell-engaging bispecific antibodies (TCBs) directed against the PAX8 lineage-driven HGSOC tumor antigen LYPD1 and demonstrated that anti-LYPD1 TCBs induce T cell activation and promote in vivo tumor growth inhibition in LYPD1-expressing HGSOC. To selectively target LYPD1-expressing tumor cells with high expression while sparing cells with low expression, we coupled bivalent low-affinity anti-LYPD1 Fabs with the anti-CD3 SP34 scFv. In contrast to the monovalent anti-LYPD1 high-affinity TCB (VHP354), the bivalent low-affinity anti-LYPD1 TCB (QZC131) demonstrated antigen density-dependent selectivity and showed tolerability in cynomolgus monkeys at the maximum dose tested of 3 mpk. Collectively, these data demonstrate that bivalent TCBs directed against LYPD1 have compelling efficacy and safety profiles supportive of consideration for treatment of high-grade serous ovarian cancers.
Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
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