AT1413 ANTIBODY DERIVED FROM A CURED AML PATIENT RECOGNIZES A UNIQUE CD43 EPITOPE SHARED BY AML, MDS AND MELANOMA AND HAS IN VIVO ACTIVITY AS UNMODIFIED ANTIBODY AND AS BISPECIFIC T CELL ENGAGER
Author(s): ,
Greta De Jong
Affiliations:
Amsterdam UMC,Amsterdam,Netherlands;AIMM Therapeutics,Amsterdam,Netherlands;Cancer Center Amsterdam,Amsterdam,Netherlands
,
Lina Bartels
Affiliations:
AIMM Therapeutics,Amsterdam,Netherlands;Amsterdam UMC,Amsterdam,Netherlands
,
Martijn Kedde
Affiliations:
AIMM Therapeutics,Amsterdam,Netherlands
,
Els Verdegaal
Affiliations:
LUMC,Leiden,Netherlands
,
Etsuko Yasuda
Affiliations:
AIMM Therapeutics,Amsterdam,Netherlands
,
Pauline van Helden
Affiliations:
AIMM Therapeutics,Amsterdam,Netherlands
,
Koen Wagner
Affiliations:
AIMM Therapeutics,Amsterdam,Netherlands
,
Remko Schotte
Affiliations:
AIMM Therapeutics,Amsterdam,Netherlands
,
Hergen Spits
Affiliations:
AIMM Therapeutics,Amsterdam,Netherlands
Mette Hazenberg
Affiliations:
Amsterdam UMC,Amsterdam,Netherlands;Cancer Center Amsterdam,Amsterdam,Netherlands
EHA Library. de Jong G. Jun 15, 2019; 267272; PS971
Greta de Jong
Greta de Jong
Contributions
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Abstract

Abstract: PS971

Type: Poster Presentation

Presentation during EHA24: On Saturday, June 15, 2019 from 17:30 - 19:00

Location: Poster area

Background
By searching the donor-derived B cell repertoire of AML patients who remain in long term remission following allogeneic hematopoietic stem cell transplantation we identified an antibody (AT1413) that recognizes a sialylated epitope on CD43. This CD43s is expressed on myeloid cells but not on B and T cells and is over-expressed on acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) cells. AT1413 kills AML cells in vitro and in vivo via antibody dependent cell-mediated cytotoxicity (ADCC) suggesting that AT1413 played a role in the graft versus leukemia response of this patient. 

Aims
Because CD43 is broadly expressed in non-hematopoietic cells we explored whether CD43s is present on non-hematopoietic tumors. To potentiate the cytotoxic abilities of the antibody even more, we developed the antibody into a bispecific T cell engaging antibody (bTCE).

Methods
AT1413 binding on a panel of tumor cell lines was analyzed by flow cytometry. AT1413 was assembled into a bispecific T-cell engaging format (AT1413 bTCE) by linking the full-length AT1413 IgG to two single chain variable fragments against CD3e with a combination of site-specific enzymatic and chemical coupling. Two point-mutations in the IgG heavy chain (G236R, L328R) were introduced to prevent interactions between AT1413 bTCE and Fcg-receptors. The cytotoxicity-inducing activities of the unmodified AT1413 antibody and its bTCE format were tested with PBMCs or cultured T cells as effector and tumor cells as target cells using standard cytotoxic assays. AT1413 bTCE was tested in vivo in a humanized immune system (HIS) mouse model engrafted with the human SH2 cell line and subsequently in two patient-derived xenograft AML mouse models.

Results
AT1413 bound to melanoma cell lines but not to pancreas, colon or liver carcinoma. Expression on melanoma cells was confirmed by immunoprecipitation and western blot using a mouse anti-human CD43 antibody. AT1413 bound to 14 out of 21 patient-derived primary melanoma samples with varying intensities. AT1413 induced ADCC of melanoma cell lines and patient-derived melanoma cells. The level of ADCC correlated with CD43s expression levels. Concomitantly, AT1413 bTCE induced strong cytotoxic T cell activities against AML and melanoma cell lines in vitro. In vivo, AT1413 bTCE induced potent tumor growth inhibition in both AML mouse models compared with a control bTCE. In the HIS mouse model, AT1413 bTCE treatment did not affect normal human hematopoiesis. The in vivo effect of the AT1413 bTCE against melanoma is currently being examined.

Conclusion
We identified a novel tumor-target, a sialylated epitope on CD43, that was identified on AML cells but is shared by melanoma and MDS cells. Targeting this epitope by the non-modified IgG antibody AT1413 and the bispecific TCE form of AT1413 induce strong anti-tumor cytotoxic activities in vitro and in vivo. Because of its broad tumor reactivity and functional activities in the absence of obvious hematopoietic toxicity, AT1413 has promising therapeutic potential.

Session topic: 3. Acute myeloid leukemia - Biology & Translational Research

Keyword(s): Allogeneic hematopoietic stem cell transplant, AML, Graft-versus-leukemia

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