Human recombinant anti-thyroperoxidase autoantibodies: in vitro cytotoxic activity on papillary thyroid cancer expressing TPO

Abstract

BACKGROUND: Thyroid cancers are difficult to treat due to their limited responsiveness to chemo-and radiotherapy. There is thus a great interest in and a need for alternative therapeutic approaches. RESULTS: We studied the cytotoxic activity of anti-thyroperoxidase autoantibodies (anti-TPO aAbs, expressed in baculovirus/insect cell (B4) and CHO cells (B4 0 ) or purified from patients' sera) against a papillary thyroid cancer (NPA) cell line. Anti-TPO aAbs from patients' sera led to a partial destruction of NPA cell line by complement-dependent cytotoxicity (CDC) and antibody-dependent cell-mediated cytotoxicity (ADCC) and exhibited an anti-proliferative activity. Comparison of the cytotoxic activity of anti-TPO aAbs shows that B4 0 induced an anti-proliferative effect and a better ADCC than B4, but a lower one than anti-TPO aAbs from patients' sera. Antibody-dependent cell-mediated cytotoxicity was increased when human peripheral blood mononuclear cells were used as effector cells, suggesting that FcgRs, CD64, CD32 and CD16 are involved. Indeed, anti-TPO aAbs from patients' sera, but not B4 and B4 0 , exhibited CDC activity. CONCLUSIONS: These data indicate that anti-TPO aAbs display moderate ADCC and anti-proliferative activities on NPA cells; IgG glycosylation appears to be important for cytotoxic activity and ADCC efficiency depends on FcgR-bearing cells. Finally, recombinant human anti-TPO aAbs cannot yet be considered as an optimal tool for the development of a novel therapeutic approach for thyroid cancer.

Decreased IgG core fucosylation, a player in antibody-dependent cell-mediated cytotoxicity, is associated with autoimmune thyroid diseases

“…Interestingly, ADCC was previously reported in AITD without restriction to subgroups of patients, however, more patients with HT than with GD presented ADCC activities 52,53 . Although no strong correlation of TPOAb level (total IgG or IgG subclasses) measured by enzyme-linked immunosorbent assay (ELISA) with ADCC activity could be found in previous studies, and other thyroid antigens besides TPO could be involved in ADCC, TPO was described as the primary antigen involved in the thyroid ADCC [52][53][54][55] . Deglycosylation of TPOAb was shown to reduce the binding to FcγRs and thus inhibit the apoptosis of thyroid cancer cells via complement-dependent cytotoxicity (CDC) and cytotoxicity via ADCC 54 .…”

“…Although no strong correlation of TPOAb level (total IgG or IgG subclasses) measured by enzyme-linked immunosorbent assay (ELISA) with ADCC activity could be found in previous studies, and other thyroid antigens besides TPO could be involved in ADCC, TPO was described as the primary antigen involved in the thyroid ADCC [52][53][54][55] . Deglycosylation of TPOAb was shown to reduce the binding to FcγRs and thus inhibit the apoptosis of thyroid cancer cells via complement-dependent cytotoxicity (CDC) and cytotoxicity via ADCC 54 . Although IgG glycosylation studied in the present paper is of total and not antigen-specific IgG, we found a relationship between TPOAb level and IgG core fucose, and we suggest that the depletion of core fucose observed in TPOAb circulating in blood could enhance their cytotoxicity activities on thyrocytes through ADCC (Fig.…”

A Mouse Monoclonal Antibody against Dengue Virus Type 1 Mochizuki Strain Targeting Envelope Protein Domain II and Displaying Strongly Neutralizing but Not Enhancing Activity

“…K562 cells have only Fc␥RIIa, whereas U937 and HL60 cells express both Fc␥RI and Fc␥RIIa (45,53,54). On the other hand, Fc␥RIIa can bind to mouse IgG1, IgG2a, and IgG2b, but not IgG3, whereas Fc␥RI can bind strongly to mouse IgG2a and IgG3 (55,56).…”

Multi-omic analyses reveal antibody-dependent natural killer cell-mediated cytotoxicity in autoimmune thyroid diseases

“…In addition to the positive association of Caspase-2 with AITD, we observed an increase of its secretion in patients with hypothyroidism and euthyroidism/TPOAb-positive. As TPOAb has been proposed to promote ADCC against thyroid cells 4, 10, 18, 19, 69 , the Caspase-2 protein may represent a marker signifying the destruction of thyroid cells by TPOAb. The IL-1α protein, on the other hand, is a member of the interleukin 1 cytokine family and is produced mainly by activated immune cells as well epithelial and endothelial cells in response to cell injury and induces apoptosis.…”