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Genomic determinants of response and resistance to inotuzumab ozogamicin in B-cell ALL
Open accessPreprint — published as 10.1182/blood.2024023930 · Paper page
Abstract
Inotuzumab ozogamicin (InO) is an antibody-drug conjugate that delivers calicheamicin to CD22-expressing cells. In a retrospective cohort of InO treated patients with B-cell acute lymphoblastic leukemia, we sought to understand the genomic determinants of response to InO. Acquired CD22 mutations were observed in 11% (3/27) of post-InO relapsed tumor samples. There were multiple CD22 mutations per sample and the mechanisms of CD22 escape included protein truncation, protein destabilization, and epitope alteration. Hypermutation by error-prone DNA damage repair (alternative end-joining, mismatch repair deficiency) drove CD22 escape. Acquired loss-of-function mutations in TP53 , ATM and CDKN2A were observed, suggesting compromise of the G1/S DNA damage checkpoint as a mechanism of evading InO-induced apoptosis. In conclusion, genetic alterations modulating CD22 expression and DNA damage response influence InO efficacy. The escape strategies within and beyond antigen loss to CD22-targeted therapy elucidated in this study provide insights into improving therapeutic approaches and overcoming resistance. KEY POINTS: We identified multiple mechanisms of CD22 antigen escape from inotuzumab ozogamicin, including protein truncation, protein destabilization, and epitope alteration. Hypermutation caused by error-prone DNA damage repair was a driver of CD22 mutation and escape. VISUAL ABSTRACT:
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Metadata
- Authors
- Zhao, Y., Short, N. J., Kantarjian, H. M., Chang, T.-C., Ghate, P. S., Qu, C., Macaron, W., Jain, N., Thakral, B., Phillips, A. H., Khoury, J., Garcia-Manero, G., Zhang, W., Fan, Y., Yang, H., Garris, R. S., Nasr, L. F., Kriwacki, R. W., Roberts, K. G., Konopleva, M., Jabbour, E. J., & Mullighan, C. G.
- Affiliations
- St. Jude Children's Research Hospital (US)
- The University of Texas MD Anderson Cancer Center (US)
- University of Nebraska Medical Center (US)
- Albert Einstein College of Medicine (US)
- Corresponding author
- Mullighan, Charles G
- ORCID
- Venue
- Blood
- Publisher
- openRxiv
- Published
- 2023-12-09
- Volume
- 144
- Issue
- 1
- Pages
- 61-73
- ISSN
- 0006-4971 (ISSN-L)
- PMC
- PMC10723521
- OpenAlex
- W4393307256
- Cited by
- 41
- References
- 1
- Citations by year
- 2026: 15 · 2025: 20 · 2024: 6
- FWCI
- 16.98
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Locations
- Blood (publishedVersion)
- medRxiv (acceptedVersion)
- PubMed (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed Central (submittedVersion)
- Digital Commons-TMC (Texas Medical Center) (submittedVersion)
- Funders
- Pfizer
- St. Jude Children's Research Hospital (CA021765, P30 CA021765)
- American Lebanese Syrian Associated Charities (CA021765)
- National Institutes of Health (CA 021765)
- University of Texas MD Anderson Cancer Center
- National Cancer Institute (CA021765, CA197695, R35CA197695, P30CA021765)
- Topics
- Health Sciences › Medicine › Hematology › Acute Lymphoblastic Leukemia research
- Health Sciences › Medicine › Oncology › CAR-T cell therapy research
- Health Sciences › Medicine › Hematology › Chronic Lymphocytic Leukemia Research
- Keywords
- inotuzumab ozogamicin, B-cell acute lymphoblastic leukemia, acquired drug resistance, epitope loss, DNA repair, hypermutation, TP53, ATM, CDKN2A, terminal deoxynucleotidyl transferase, hematopoietic stem cell transplantation, CRISPR-Cas9 screen, calicheamicin, antibody-drug conjugates, G1/S checkpoint, residual disease
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