High-valency Anti-CD99 Antibodies Toward the Treatment of T Cell Acute Lymphoblastic Leukemia

Romero, Larizbeth A.; Hattori, Takamitsu; Ali, Mohamed Ashraf; Ketavarapu, Gayatri; Park, Christopher Y.; Koide, Shohei

doi:10.1016/j.jmb.2021.167402

Cited by 5 publications

(16 citation statements)

References 82 publications

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“…However, multiple essential aspects need to be assessed before clinical translation of a targeted tracer, such as comprehensive evaluation of biodistribution, toxicology, determination of optimal dosage and safety, and subsequent registration as an approved drug. It is worth noting that fully humanized monoclonal antibodies and single-chain variable fragment (scFv) against CD99 are already available and have exhibited minimal toxicity to healthy peripheral blood cells [37]. Ideally, the smaller anti-CD99 scFv should be transformed into a clinical tracer by conjugation to a NIR fluorophore.…”

Section: Discussionmentioning

confidence: 99%

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Evaluation of Potential Targets for Fluorescence-Guided Surgery in Pediatric Ewing Sarcoma: A Preclinical Proof-of-Concept Study

Jeremiasse,

Rijs,

Angoelal

et al. 2023

Cancers

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Fluorescence-guided surgery (FGS), based on fluorescent tracers binding to tumor-specific biomarkers, could assist surgeons to achieve complete tumor resections. This study evaluated potential biomarkers for FGS in pediatric Ewing sarcoma (ES). Immunohistochemistry (IHC) was performed to assess CD99, CXCR4, CD117, NPY-R-Y1, and IGF-1R expression in ES biopsies and resection specimens. LINGO-1 and GD2 evaluation did not work on the acquired tissue. Based on the immunoreactive scores, anti-CD99 and anti-CD117 were evaluated for binding specificity using flow cytometry and immunofluorescence microscopy. Anti-GD2, a tracer in the developmental phase, was also tested. These three tracers were topically applied to a freshly resected ES tumor and adjacent healthy tissue. IHC demonstrated moderate/strong CD99 and CD117 expression in ES tumor samples, while adjacent healthy tissue had limited expression. Flow cytometry and immunofluorescence microscopy confirmed high CD99 expression, along with low/moderate CD117 and low GD2 expression, in ES cell lines. Topical anti-CD99 and anti-GD2 application on ES tumor showed fluorescence, while anti-CD117 did not show fluorescence for this patient. In conclusion, CD99-targeting tracers hold promise for FGS of ES. CD117 and GD2 tracers could be potential alternatives. The next step towards development of ES-specific FGS tracers could be ex vivo topical application experiments on a large cohort of ES patients.

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Section: Discussionmentioning

confidence: 99%

“…Ideally, the smaller anti-CD99 scFv should be transformed into a clinical tracer by conjugation to a NIR fluorophore. This approach would enable the achievement of a high TBR within hours after IV administration, compared to days required for large-sized antibodies [16,37].…”

Section: Discussionmentioning

confidence: 99%

Evaluation of Potential Targets for Fluorescence-Guided Surgery in Pediatric Ewing Sarcoma: A Preclinical Proof-of-Concept Study

Jeremiasse,

Rijs,

Angoelal

et al. 2023

Cancers

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“…The engagement of Ad20 epitopes swiftly triggers T cell death through a caspase-independent pathway. Recently, Romero et al [ 57 ] developed the human anti-CD99 antibody clone 10A1, which binds to CD99 residues 63–76, and engineered it into a tetravalent version. The study highlighted the crucial role of antibody valency in ligation of CD99 inducing cytotoxicity.…”

Section: Direct Effects Of Mabs Against Cd99 In T-allmentioning

confidence: 99%

“…However, antibodies with a valency of three or more are required for inducing cytotoxicity on T-ALL cells. This finding suggests that at least three CD99 molecules need to be clustered by the antibody to induce cytotoxicity [ 57 ]. Although multivalent antibodies are required for inducing the apoptotic pathway of CD99 in T-ALL.…”

Section: Direct Effects Of Mabs Against Cd99 In T-allmentioning

confidence: 99%

CD99 tumor associated antigen is a potential target for antibody therapy of T-cell acute lymphoblastic leukemia

Kotemul,

Kasinrerk,

Takheaw

2024

Exploration of Targeted Anti-Tumor Therapy

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Monoclonal antibodies (mAbs) are an effective drug for targeted immunotherapy in several cancer types. However, so far, no antibody has been successfully developed for certain types of cancer, including T-cell acute lymphoblastic leukemia (T-ALL). T-ALL is an aggressive hematologic malignancy. T-ALL patients who are treated with chemotherapeutic drugs frequently relapse and become drug resistant. Therefore, antibody-based therapy is promising for T-ALL treatment. To successfully develop an antibody-based therapy for T-ALL, antibodies that induce death in malignant T cells but not in nonmalignant T cells are required to avoid the induction of secondary T-cell immunodeficiency. In this review, CD99 tumor associated antigen, which is highly expressed on malignant T cells and lowly expressed on nonmalignant T cells, is proposed to be a potential target for antibody therapy of T-ALL. Since certain clones of anti-CD99 mAbs induce apoptosis only in malignant T cells, these anti-CD99 mAbs might be a promising antibody drug for the treatment of T-ALL with high efficiency and low adverse effects. Moreover, over the past 25 years, many clones of anti-CD99 mAbs have been studied for their direct effects on T-ALL. These outcomes are gathered here.

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“…Currently, CD99 has been demonstrated to be a potential target for antibody therapy on T-ALL with less toxicity to normal blood cells [ 10 , 11 ]. It has been reported that targeting CD99 by certain clones of anti-CD99 mAb induced cell apoptosis of malignant T cells but not in non-malignant T cells [ 12 , 13 , 14 ]. However, there remains a lack of knowledge on which epitope on the CD99 molecule contributes to the apoptosis of T-ALL upon anti-CD99 mAb engagement.…”

Section: Introductionmentioning

confidence: 99%

Transcriptome Analysis Reveals the Induction of Apoptosis-Related Genes by a Monoclonal Antibody against a New Epitope of CD99 on T-Acute Lymphoblastic Leukemia

Takheaw,

Kotemul,

Chaiwut

et al. 2024

Antibodies

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CD99 was demonstrated to be a potential target for antibody therapy on T-acute lymphoblastic leukemia (T-ALL). The ligation of CD99 by certain monoclonal antibodies (mAbs) induced T-ALL apoptosis. However, the molecular basis contributing to the apoptosis of T-ALL upon anti-CD99 mAb engagement remains elusive. In this study, using our generated anti-CD99 mAb clone MT99/3 (mAb MT99/3), mAb MT99/3 engagement strongly induced apoptosis of T-ALL cell lines, but not in non-malignant peripheral blood cells. By transcriptome analysis, upon mAb MT99/3 ligation, 13 apoptosis-related genes, including FOS, TNF, FASLG, BCL2A1, JUNB, SOCS1, IL27RA, PTPN6, PDGFA, NR4A1, SGK1, LPAR5 and LTB, were significantly upregulated. The epitope of CD99 recognized by mAb MT99/3 was then identified as the VDGENDDPRPP at residues 60–70 of CD99, which has never been reported. To the best of our knowledge, this is the first transcriptome data conducted in T-ALL with anti-CD99 mAb engagement. These findings provide new insights into CD99 implicated in the apoptosis of T-ALL. The identification of a new epitope and apoptosis-related genes that relate to the induction of apoptosis by mAb MT99/3 may serve as a new therapeutic target for T-ALL. The anti-CD99 mAb clone MT99/3 might be a candidate for further development of a therapeutic antibody for T-ALL therapy.

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High-valency Anti-CD99 Antibodies Toward the Treatment of T Cell Acute Lymphoblastic Leukemia

Cited by 5 publications

References 82 publications

Evaluation of Potential Targets for Fluorescence-Guided Surgery in Pediatric Ewing Sarcoma: A Preclinical Proof-of-Concept Study

Evaluation of Potential Targets for Fluorescence-Guided Surgery in Pediatric Ewing Sarcoma: A Preclinical Proof-of-Concept Study

CD99 tumor associated antigen is a potential target for antibody therapy of T-cell acute lymphoblastic leukemia

Transcriptome Analysis Reveals the Induction of Apoptosis-Related Genes by a Monoclonal Antibody against a New Epitope of CD99 on T-Acute Lymphoblastic Leukemia

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