Efficient targeting of CD13 on cancer cells by the immunotoxin scFv13–ETA′ and the bispecific scFv [13xds16]

Grieger, Elena; Gresch, Gerrit; Niesen, Judith; Woitok, Mira; Barth, Stefan; Fischer, Rainer; Fendel, Rolf; Stein, Christoph

doi:10.1007/s00432-017-2468-5

Cited by 10 publications

(8 citation statements)

References 46 publications

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“…[53][54][55][56] CD13 has also been investigated as a target for cancer therapy. 57 These anti-membrane antibodies generated in cGVHD patients can not only target affected tissues such as skin keratinocytes but can also target leukemia cells, due to the overlapping expression of the targeted antigens on leukemia cells. In addition to T cells targeting antigens expressed on leukemia cells and normal tissues, these findings provide another potential mechanism by which cGVHD is associated with GVL.…”

Section: Discussionmentioning

confidence: 99%

Antibodies targeting surface membrane antigens in patients with chronic graft-versus-host disease

Wang¹,

Kim

Nikiforow³

et al. 2017

Blood

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Chronic graft-versus-host disease (cGVHD) after allogeneic hematopoietic stem cell transplant reflects a complex immune response resulting in chronic damage to multiple tissues. Previous studies indicated that donor B cells and the antibodies they produce play an important role in the development of cGVHD. To understand the pathogenic role of antibodies in cGVHD, we focused our studies on posttransplant production of immunoglobulin G antibodies targeting cell surface antigens expressed in multiple cGVHD affected tissues, due to their potential functional impact on living cells in vivo. Using plate-bound cell membrane proteins as targets, we detected a significantly higher level of antibodies reactive with these membrane antigens in patients who developed cGVHD, compared with those who did not and healthy donors. Plasma-reactive antibody levels increased significantly prior to the clinical diagnosis of cGVHD and were reduced following cGVHD therapies including prednisone, interleukin-2, or extracorporeal photophoresis. Using cell-based immunoprecipitation with plasma from cGVHD patients and mass spectrometry, we identified 43 membrane proteins targeted by these antibodies. The presence of antibodies in cGVHD patients' plasma that specifically target 6 of these proteins was validated. Antibodies reactive with these 6 antigens were more frequently detected in patients with cGVHD compared with patients without cGVHD and healthy donors. These results indicate that antibodies that target membrane antigens of living cells frequently develop in cGVHD patients and further support a role for B cells and antibodies in the development of cGVHD.

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Section: Discussionmentioning

confidence: 99%

Antibodies targeting surface membrane antigens in patients with chronic graft-versus-host disease

Wang¹,

Kim

Nikiforow³

et al. 2017

Blood

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“…Likewise, such sequence has been used for the preparation of a prodrug of melphalan (melflufen or "J1", [3]) which is currently undergoing clinical trials for multiple myeloma. Of note is that a single CD13-specific single-chain V-Ig-fragment (scFv13) linked to exotoxin A from Pseudomonas aeruginosa has been probed to inhibit proliferation of human cancer cell lines in vitro [48]. However, development of standard ADC targeting CD13 has been neglected.…”

Section: Discussionmentioning

confidence: 99%

CD13 as a new tumor target for antibody-drug conjugates: validation with the conjugate MI130110

et al. 2020

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Background: In the search for novel antibody-drug conjugates (ADCs) with therapeutic potential, it is imperative to identify novel targets to direct the antibody moiety. CD13 seems an attractive ADC target as it shows a differential pattern of expression in a variety of tumors and cell lines and it is internalized upon engagement with a suitable monoclonal antibody. PM050489 is a marine cytotoxic compound tightly binding tubulin and impairing microtubule dynamics which is currently undergoing clinical trials for solid tumors. Methods: Anti-CD13 monoclonal antibody (mAb) TEA1/8 has been used to prepare a novel ADC, MI130110, by conjugation to the marine compound PM050489. In vitro and in vivo experiments have been carried out to demonstrate the activity and specificity of MI130110. Results: CD13 is readily internalized upon TEA1/8 mAb binding, and the conjugation with PM050489 did not have any effect on the binding or the internalization of the antibody. MI130110 showed remarkable activity and selectivity in vitro on CD13-expressing tumor cells causing the same effects than those described for PM050489, including cell cycle arrest at G2, mitosis with disarrayed and often multipolar spindles consistent with an arrest at metaphase, and induction of cell death. In contrast, none of these toxic effects were observed in CD13-null cell lines incubated with MI130110. Furthermore, in vivo studies showed that MI130110 exhibited excellent antitumor activity in a CD13-positive fibrosarcoma xenograft murine model, with total remissions in a significant number of the treated animals. Mitotic catastrophes, typical of the payload mechanism of action, were also observed in the tumor cells isolated from mice treated with MI130110. In contrast, MI130110 failed to show any activity in a xenograft mouse model of myeloma cells not expressing CD13, thereby corroborating the selectivity of the ADC to its target and its stability in circulation.

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“…Finally, CD13 is considered a viable target for cancer therapy [ 10 , 28 ] in view of its participation in processes such as angiogenesis, tumor cell migration, and invasiveness, and the fact that expression of CD13 is dysregulated in several types of cancer cells, contributing in several ways to the malignancy. Several drugs interfering with CD13 functions are being tested for the development of anticancer drugs [ 1 , 29 – 32 ]. In this respect, some properties of mAbs C and E, such as the strong inhibition of enzymatic activity and the ability to inhibit cell attachment to extracellular matrix proteins, deserve further study because of their potential to be exploited in cancer therapy.…”

Section: Discussionmentioning

confidence: 99%

Distinct Epitopes on CD13 Mediate Opposite Consequences for Cell Adhesion

Garay-Canales

Licona‐Limón

Ortega

2018

BioMed Research International

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CD13 is a membrane glycoprotein with aminopeptidase activity, expressed on several cell types, including myeloid cells (dendritic cells, monocytes, macrophages, neutrophils, etc.). CD13 participates in several functions such as proteolytic regulation of bioactive peptides, viral receptor, angiogenesis, and tumor metastasis. CD13 has also been proposed to participate in cell adhesion, as crosslinking of CD13 by certain CD13-specific antibodies induces homotypic aggregation of monocytes and heterotypic adhesion of monocytes to endothelial cells. We generated two monoclonal antibodies (mAbs C and E) that block homotypic aggregation of U-937 monocytic cells induced by CD13-specific mAb 452. Moreover, the mAbs cause detachment of cells whose aggregation was induced by CD13 crosslinking. Both mAbs also inhibit heterotypic adhesion of U-937 monocytes to endothelial cells. mAbs C and E recognize membrane CD13 but bind to epitopes different from that recognized by mAb 452. Crosslinking of CD13 by mAb C or E is required to inhibit adhesion, as monovalent Fab fragments are not sufficient. Thus, C and E antibodies recognize a distinct epitope on CD13, and binding to this epitope interferes with both CD13-mediated cell adhesion and enzymatic activity. These antibodies may represent important tools to study cell-cell interactions mediated by CD13 in physiological and pathological conditions.

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Efficient targeting of CD13 on cancer cells by the immunotoxin scFv13–ETA′ and the bispecific scFv [13xds16]

Cited by 10 publications

References 46 publications

Antibodies targeting surface membrane antigens in patients with chronic graft-versus-host disease

Antibodies targeting surface membrane antigens in patients with chronic graft-versus-host disease

CD13 as a new tumor target for antibody-drug conjugates: validation with the conjugate MI130110

Distinct Epitopes on CD13 Mediate Opposite Consequences for Cell Adhesion

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