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Fc gamma receptor is not required for in vivo processing of radio- and drug-conjugates of the dead tumor cell-targeting monoclonal antibody, APOMAB® - 03/06/22

Doi : 10.1016/j.biopha.2022.113090 
Alexander H. Staudacher a, b, , Vasilios Liapis a, Nicole L. Wittwer a, William Tieu b, c, Hiu Chun Lam c, Jeanette Leusen d, Michael P. Brown a, b, e
a Translational Oncology Laboratory, Centre for Cancer Biology, SA Pathology and University of South Australia, Adelaide, SA 5000, Australia 
b School of Medicine, University of Adelaide, Adelaide, SA 5000, Australia 
c Molecular Imaging and Therapy Research Unit, South Australian Health and Medical Research Institute (SAHMRI), Adelaide, SA 5000, Australia 
d Immunotherapy Laboratory, Center for Translational Immunology, University Medical Center Utrecht, Utrecht, The Netherlands 
e Cancer Clinical Trials Unit, Royal Adelaide Hospital, Adelaide, SA 5000, Australia 

Correspondence to: Translational Oncology Laboratory, Centre for Cancer Biology, Level 9 University of South Australia Bradley Building, North Terrace, Adelaide 5000, Australia.Translational Oncology Laboratory, Centre for Cancer BiologyLevel 9 University of South Australia Bradley Building, North TerraceAdelaide5000Australia

Abstract

The Fc region of a monoclonal antibody (mAb) can play a crucial role in its biodistribution and therapeutic activity. The chimeric mAb, chDAB4 (APOMAB®), which binds to dead tumor cells after DNA-damaging anticancer treatment, has been studied pre-clinically in both diagnostic and therapeutic applications in cancer. Given that macrophages contribute to the tumor accumulation of chDAB4 and its potency as an antibody drug conjugate in vivo, we next wanted to determine whether the Fc region of the chDAB4 mAb also contributed. We found that, regardless of prior labeling with chDAB4, dead EL4 lymphoma or Lewis Lung (LL2) tumor cells were phagocytosed equally by wild-type or Fcγ knock-down macrophage cell lines. A similar result was seen with bone marrow-derived macrophages from wild-type, Fcγ knock-out (KO) and NOTAM mice that express Fcγ but lack immunoreceptor tyrosine-based activation motif (ITAM) signaling. Among EL4 tumor-bearing wild-type, Fcγ KO or NOTAM mice, no differences were observed in post-chemotherapy uptake of 89Zr-labeled chDAB4. Similarly, no differences were observed between LL2 tumor-bearing wild-type and Fcγ KO mice in post-chemotherapy uptake of 89Zr-chDAB4. Also, the post-chemotherapy activity of a chDAB4-antibody drug conjugate (ADC) directed against LL2 tumors did not differ among tumor-bearing wild-type, Fcγ KO and NOTAM mice, nor did the proportions and characteristics of the LL2 tumor immune cell infiltrates differ significantly among these mice. In conclusion, Fc-FcγR interactions are not essential for the diagnostic or therapeutic applications of chDAB4 conjugates because the tumor-associated macrophages, which engulf the chDAB4-labelled dead cells, respond to endogenous ‘eat me’ signals rather than depend on functional FcγR expression for phagocytosis.

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Graphical Abstract

The mAb-binding FcγR is not required for processing of the chDAB4 mAb.
Macrophages phagocytose chDAB4-bound dead cancer cells independently of Fc-FcγR interactions.


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El texto completo de este artículo está disponible en PDF.

Highlights

The antibody-binding FcγR is not required for processing of the chDAB4 monoclonal antibody.
Macrophages phagocytose chDAB4-bound dead cancer cells independently of Fc-FcγR interactions.
Fc-FcγR interactions are not essential for diagnostic or therapeutic applications of chDAB4.

El texto completo de este artículo está disponible en PDF.

Keywords : NOTAM, FcγR, APOMAB, ChDAB4, Zirconium-89, PBD dimer


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© 2022  The Authors. Publicado por Elsevier Masson SAS. Todos los derechos reservados.
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Vol 151

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