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Melanoma cells can be eliminated by sialylated CD43 × CD3 bispecific T cell engager formats in vitro and in vivo

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Abstract

Targeted cancer therapy with monoclonal antibodies has proven successful for different cancer types but is limited by the availability of suitable antibody targets. CD43s, a unique sialylated form of CD43 expressed by hematologic malignancies, is a recently identified target and antibodies interacting with CD43s may have therapeutic potential against acute myeloid leukemia (AML) and myelodysplastic syndrome. CD43s is recognized by the human antibody AT1413, that was derived from a high-risk AML patient who successfully cleared leukemia after allogeneic stem cell transplantation. Here we observed that AT1413 binds also to certain non-hematopoietic tumor cells, particularly melanoma and breast cancer. AT1413 immune precipitated CD43s from melanoma cells confirming that it recognizes the same target on melanoma as on AML. AT1413 induced antibody-dependent cellular cytotoxicity against short-term cultured patient-derived melanoma samples. However, AT1413 was unable to affect the growth of melanoma cells in vivo. To increase the efficacy of AT1413 as a therapeutic antibody, we generated two different formats of bispecific T-cell engaging antibodies (TCEs): one binding bivalently (bTCE) and the other monovalently (knob-in-hole; KiH) to both CD43s and CD3ε. In vitro, these TCEs redirected T-cell cytotoxicity against melanoma cells with differences in potencies. To investigate their effects in vivo, we grafted mice that harbor a human immune system with the melanoma cell line A375. Treatment with both AT1413 bTCE and AT1413 KiH significantly reduced tumor outgrowth in these mice. These data indicate a broad therapeutic potential of AT1413 that includes AML and CD43s-expressing solid tumors that originate from CD43-negative tissues.

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Abbreviations

bTCE:

Bivalent TCE

CD43s:

Sialylated CD43

E:T:

Effector-to-target cell

HIS:

Human immune system

IP:

Immunoprecipitated

KiH:

Knob-in-hole

pMHC:

Peptide MHC

SPL:

Spleen

TCE:

T-cell engager

TUM:

Tumor

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Acknowledgements

The authors are greatly indebted to the patients who participated in this study.

Funding

GdJ is financially supported by the Dutch Cancer Society (KWF 2014-6557). LBA is financially supported by a Zwaartekracht grant to HS from the Netherlands Organization for Scientific Research (NWO ICI00004). RS and CF are financially supported by the Dutch Cancer Society (UVA 2010-4822). MDH is supported by a VIDI grant by the Netherlands Organization for Health Research and Development (NWO ZonMW 91715362) and by a Fellowship of the Landsteiner Foundation for Blood Transfusion Research (LSBR 1438F).

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Author notes

  1. G. de Jong and L. Bartels have contributed equally to this work.

Authors and Affiliations

  1. AIMM Therapeutics, Meibergdreef 59, 1105 BA, Amsterdam, The Netherlands

    G. de Jong, L. Bartels, M. Kedde, M. A. Gillissen, S. E. Levie, M. G. Cercel, S. E. van Hal-van Veen, C. Fatmawati, D. van de Berg, E. Yasuda, Y. B. Claassen, A. Q. Bakker, R. Schotte, J. Villaudy, H. Spits, P. M. van Helden & K. Wagner

  2. Department of Hematology, Amsterdam UMC, Location AMC, Amsterdam, The Netherlands

    G. de Jong, M. A. Gillissen & M. D. Hazenberg

  3. Cancer Center Amsterdam (CCA), Amsterdam, The Netherlands

    G. de Jong, M. A. Gillissen & M. D. Hazenberg

  4. Amsterdam Infection and Immunity Institute (AI&II), Amsterdam, The Netherlands

    G. de Jong, L. Bartels, M. A. Gillissen, H. Spits & M. D. Hazenberg

  5. Department of Medical Oncology, Oncode Institute, Leiden University Medical Center, Leiden, The Netherlands

    E. M. E. Verdegaal & S. H. van der Burg

  6. Department of Experimental Immunology, Amsterdam UMC, Location AMC, Amsterdam, The Netherlands

    H. Spits

  7. Department of Hematopoiesis, Sanquin Research, Amsterdam, The Netherlands

    M. D. Hazenberg

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  1. G. de Jong
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  2. L. Bartels
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  4. E. M. E. Verdegaal
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  7. M. G. Cercel
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  8. S. E. van Hal-van Veen
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Contributions

Conceptualization: HS, MDH, KW and PMH; methodology: GJ, LB, MK, EMEV, MAG, EY, AQB, JV and KW; formal analysis and investigation: GJ, LB, RS, MK, EMEV, EY, SEL, MGC, SEHV and CF; writing—original draft preparation: GJ and LB; writing—review and editing: MDH, HS, KW and PMH; funding acquisition: MDH, HS and KW; resources: EMEV, AQB, SHB, YBC and DB; supervision: HS, MDH and PMH

Corresponding author

Correspondence to P. M. van Helden.

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Conflict of interest

MK, SEL, MGC, SEHV, CF, DB, EY, YBC, AQB, RS, JV, HS and PMH, have ownership interests in AIMM Therapeutics. MK, MAG, PMH, MDH and HS are inventors on patent WO2016209079A1.

Ethical approval

All animal procedures were carried out in accordance with Dutch and European laws and the institutional guidelines of the Amsterdam UMC. Experiments were approved by the animal experimental committee Amsterdam (DEC) and the central committee for animal experiments (CCD) under license AVD118002016795.

Consent to participate

Patient-derived melanoma samples were isolated with approval of the Medical Ethical Committee of the Leiden University Medical Center after obtaining informed consent, under LUMC study number P04.085.

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de Jong, G., Bartels, L., Kedde, M. et al. Melanoma cells can be eliminated by sialylated CD43 × CD3 bispecific T cell engager formats in vitro and in vivo. Cancer Immunol Immunother 70, 1569–1581 (2021). https://doi.org/10.1007/s00262-020-02780-9

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