Patient-derived antibody recognizes a unique CD43 epitope expressed on all AML and has antileukemia activity in mice

Gillissen, Marijn A.; Jong, Greta de; Kedde, Martijn; Yasuda, Etsuko; Levie, Sophie E.; Moiset, Gemma; Hensbergen, Paul J.; Bakker, Arjen Q.; Wagner, Kay Uwe; Villaudy, Jullien; Helden, Pauline M. van; Spits, Hergen; Hazenberg, Mette D.

doi:10.1182/bloodadvances.2017008342

Cited by 24 publications

(26 citation statements)

References 40 publications

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“…27 Immunologic consolidation can be effective when newly infused donor immune cells that are naive with regard to the patient's AML elicit a GvL response independent of HLA-related antigen presentation, for example, to targets that are expressed on the membrane of AML blasts. 28,29 Thus, as also suggested by other studies, immunological consolidation is of importance for survival in this setting. GvHD occurred in some but not all surviving patients suggesting that immunologic consolidation can also be effective when it does not lead to GvHD.…”

Section: Discussionsupporting

confidence: 65%

Survival of early posthematopoietic stem cell transplantation relapse of myeloid malignancies

Jong

Janssen

Biemond

et al. 2019

European J of Haematology

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Objective: Relapse of AML after allogeneic hematopoietic stem cell transplantation (HSCT) has a poor prognosis, and standard of care therapy is lacking. Early (<6 months) relapse is associated with dismal outcome, while the majority of relapses occur early after transplantation. A more precise indication which patients could benefit from reinduction therapy is warranted. Methods:We retrospectively analyzed outcomes of 83 patients with postallogeneic HSCT relapse. Patients were divided based on intention to treat (curative vs supportive care). Results:Of the 50 patients treated with curative intent, 44% reached complete remission (CR) upon reinduction chemotherapy, and of these patients, 50% survived.Two survivors reached CR after immunotherapy (donor lymphocyte infusion (DLI), without reinduction chemotherapy). Sixty-nine percent of the survivors had received high-intensity cytarabine treatment, followed by immunologic consolidation. Relapse <3 months after transplantation was predictive for adverse survival (P = .004), but relapse <6 months was not. In fact, >50% of the survivors had a relapse <6 months. Conclusion:We confirmed the dismal prognosis of postallogeneic HSCT relapse.Importantly, our data demonstrate that patients fit enough to receive high-dose chemotherapy, even when relapse occurred <6 months, had the best chance to obtain durable remissions, in particular when immunologic consolidation was performed after reaching CR. K E Y W O R D S acute myeloid leukemia, allogeneic hematopoietic stem cell transplantation, graft-versusleukemia, outcome Allogeneic hematopoietic stem cell transplantation (HSCT) is the preferred treatment for patients with (MRD positive) intermediate-risk or poor-risk acute myeloid leukemia (AML) and high-risk myelodysplastic syndrome (MDS). While transplant related mortality has decreased, the risk for relapse has not. Disease relapse is a common and important cause of the poor long-term survival of allogeneic HSCT recipients with AML. Relapse accounts for 30%-40% of deaths after allogeneic HSCT, depending on the type of the donor and disease status at transplant. 1,2 Prognosis of postallogeneic HSCT AML relapse is poor 3,4 and has hardly improved in the past decades. There is no standard of care for patients who relapse after allogeneic HSCT. Age (<37 year) and a longer time (>5 months) between allogeneic HSCT and relapse have been identified as favorable prognostic factors. 3,5,6 Other factors such as clinical condition and personal considerations of the patient may be weighed in the decision to either give supportive care, offer low-dose chemotherapy, or attempt high-dose reinduction chemotherapy. In reality, curative treatment options are often limited, and in many cases, it can be more appropriate to refrain from intensive treatment regimens and opt for best supportive care. Most AML relapses occur in the first 6 months after allogeneic HSCT, a period during which many patients still receive immunosuppressive therapy. Rapid tapering of immunosuppression can potentially lead ...

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Section: Discussionsupporting

confidence: 65%

Survival of early posthematopoietic stem cell transplantation relapse of myeloid malignancies

Jong

Janssen

Biemond

et al. 2019

European J of Haematology

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“…58 Consistently, a recent study showed that patient-derived antibody recognizes a unique CD43 epitope expressed on all AML and has antileukemia activity in mice. 59 However, the mechanism of the coexpression CD5 and CD43 in the initiation, progression, and maintenance of DLBCL is currently unknown and needs further investigation.…”

Section: Discussionmentioning

confidence: 99%

Coexpression of CD5 and CD43 predicts worse prognosis in diffuse large B‐cell lymphoma

Zhong

Zheng

et al. 2018

Cancer Medicine

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Both CD5 and CD43 are expressed on the surface of B lymphocytes of definite phase and associated with the adverse outcome in diffuse large B‐cell lymphoma (DLBCL). However, the relationship between CD5 and CD43 expression and the prognostic value of CD5/CD43 coexpression in DLBCL are unknown. We herein determined the correlation between CD5 and CD43 expression, as separate factors or in combination, with the clinicopathological features and survival of 200 patients with DLBCL receiving standard chemotherapy with or without rituximab. Among these DLBCL patients, CD5 expression, CD43 expression, and CD5/CD43 coexpression were detected in 18 (9%), 57 (27%), and 10 (5%) patients, respectively, and all were positively correlated with advanced age and nongerminal cell type. CD5‐positive and CD43‐positive DLBCL patients had poorer event‐free survival (EFS, P < 0.001) and overall survival (OS, P < 0.001) than CD5‐negative and CD43‐negative patients, respectively. CD5/CD43 coexpression was correlated with a significantly worse prognosis than CD5 or CD43 expression alone. Univariate analysis showed that CD5 expression, CD43 expression, and CD5/CD43 coexpression were all adverse prognostic factors for DLBCL patient survival, and CD5/CD43 coexpression was associated with a greater relative risk for recurrence and death than either CD5 or CD43 expression alone. Multivariate analysis demonstrated that CD5/CD43 coexpression was an independent prognostic factor for EFS (P < 0.001) and OS (P < 0.001) in DLBCL. In conclusion, our data indicate that DLBCL patients with CD5/CD43 coexpression represent a specific subgroup with a significantly worse prognosis than those expressing either marker alone.

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“…Earlier, we have examined whether patients with AML successfully treated with allogeneic HSCT generate AML-specific antibodies (7)(8)(9). Allogeneic HSCT can evoke an immunotherapeutic graft-versus-leukemia reaction, which includes a B-cell response and the generation of tumor-specific antibodies (10).…”

Section: Introductionmentioning

confidence: 99%

A Chemo-enzymatically Linked Bispecific Antibody Retargets T Cells to a Sialylated Epitope on CD43 in Acute Myeloid Leukemia

et al. 2019

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Acute myeloid leukemia (AML) is a high-risk disease with a poor prognosis, particularly in elderly patients. Because current AML treatment relies primarily on untargeted therapies with severe side effects that limit patient eligibility, identification of novel therapeutic AML targets is highly desired. We recently described AT1413, an antibody produced by donor B cells of a patient with AML cured after allogeneic hematopoietic stem cell transplantation. AT1413 binds CD43s, a unique sialylated epitope on CD43, which is weakly expressed on normal myeloid cells and overexpressed on AML cells. Because of its selectivity for AML cells, we considered CD43s as a target for a bispecific T-cell-engaging antibody (bTCE) and generated a bTCE by coupling AT1413 to two T-cell-targeting fragments using chemo-enzymatic linkage. In vitro, AT1413 bTCE efficiently induced T-cell-mediated cytotoxicity toward different AML cell lines and patient-derived AML blasts, whereas endothelial cells with low binding capacity for AT1413 remained unaffected. In the presence of AML cells, AT1413 bTCE induced upregulation of T-cell activation markers, cytokine release, and T-cell proliferation. AT1413 bTCE was also effective in vivo. Mice either coinjected with human peripheral blood mononuclear cells or engrafted with human hematopoietic stem cells [human immune system (HIS) mice] were inoculated with an AML cell line or patient-derived primary AML blasts. AT1413 bTCE treatment strongly inhibited tumor growth and, in HIS mice, had minimal effects on normal human hematopoietic cells. Taken together, our results indicate that CD43s is a promising target for T-cell-engaging antibodies and that AT1413 holds therapeutic potential in a bTCE-format. Significance: These findings offer preclinical evidence for the therapeutic potential of a bTCE antibody that targets a sialylated epitope on CD43 in AML.

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Patient-derived antibody recognizes a unique CD43 epitope expressed on all AML and has antileukemia activity in mice

Abstract: Key Points AT1413 is a monoclonal antibody isolated from a cured patient with AML that recognizes CD43s, a novel epitope expressed by AML and MDS blasts. AT1413 eliminates CD43s-expressing leukemic blasts in vitro and in vivo and may have potential as a therapeutic antibody.

Cited by 24 publications

References 40 publications

Survival of early posthematopoietic stem cell transplantation relapse of myeloid malignancies

Survival of early posthematopoietic stem cell transplantation relapse of myeloid malignancies

Coexpression of CD5 and CD43 predicts worse prognosis in diffuse large B‐cell lymphoma

A Chemo-enzymatically Linked Bispecific Antibody Retargets T Cells to a Sialylated Epitope on CD43 in Acute Myeloid Leukemia

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