作者: Morère, Alain ; Taliercio, Camille ; Maynadier, Marie ; Daurat, Morgane ; Basile, Ilaria ; Gauthier, Corentin ; El Bahlagui, Iris ; Gary-Bobo, Magali ; Garcia, Marcel ; Ali, Lamiaa Mohamed Ahmed ; Morère, Elodie ; El Cheikh, Khaled

Targeted degradation of pathological proteins is a promising approach to enhance the effectiveness of therapeutic monoclonal antibodies (mAbs) in cancer therapy. In this study, we demonstrate that this objective can be efficiently achieved by the grafting of mannose 6-phosphate analogues called AMFAs² onto the therapeutic antibodies trastuzumab and cetuximab, both directed against membrane antigens. The grafting of AMFAs confers to these antibodies the novel property of being internalized via the mannose 6-phosphate receptor (M6PR) pathway. AMFA conjugation to these mAbs significantly increases their cellular uptake and leads to enhanced degradation of the target antigens in cancer cells. This results in a drastic inhibition of cancer cell proliferation compared to unconjugated mAbs, as demonstrated in various cancer cell lines, and an increased therapeutic efficacy in mouse and zebrafish xenografted models. These findings highlight the potential of this technology to improve therapeutic outcomes in cancer treatment.

2023-06-01·Journal of Controlled Release

Mannose 6-phosphate receptor-targeting antibodies preserve Fc receptor-mediated recycling

Article

作者: Basile, Ilaria ; Gauthier, Corentin ; Gouilleux-Gruart, Valerie ; Morere, Elodie ; Dhommee, Christine ; El Cheikh, Khaled ; Gary-Bobo, Magali ; Mariot, Julie ; Depaepe, Geoffrey ; Morere, Alain ; Maynadier, Marie ; Garcia, Marcel ; Daurat, Morgane

The concept of grafting mannose 6-phosphonate derivatives (M6Pn), named AMFA, on therapeutic proteins was first developed for the improvement of enzyme delivery in lysosomal storage disorders. This glycoengineering increases the cellular uptake of the protein via the cation-independent mannose 6-phosphate receptor (M6PR) which further allows their targeting to the lysosomes. In the present study, we investigated the extent to which the direct grafting of AMFA onto a drug, here a monoclonal antibody (mAb), affects the cell uptake and recycling of the antibody. The antibodies infliximab (IFX) and adalimumab (ADA), directed against the tumor necrosis factor α (TNFα), grafted with AMFA acquired an affinity for the M6PR, resulting in a >3-fold increase in drug release in cells. Subsequently, the impact of AMFA grafting to the Fc portion of mAb on its affinity for the neonatal Fc receptor (FcRn), which is the key receptor for antibody recycling, was evaluated. Whether one to three AMFA moieties were grafted, FcRn-mediated recycling of mAb was not affected. AMFA grafting did not impair the pharmacokinetics of both ADA and IFX and presented a high stability since AMFA were still bound to mAb in the plasma of mice 21 days after the treatment. In conclusion, this type of antibody engineering with a reduced number of AMFA confers M6PR targeting property and increases endocytosis, and yet appears fully compatible with FcRn binding and with antibody recycling and transcytosis.

2018-01-01·Journal of Controlled Release1区 · 医学

Efficient therapy for refractory Pompe disease by mannose 6-phosphate analogue grafting on acid α-glucosidase

1区 · 医学

Article

作者: Basile, Ilaria ; Caillaud, Catherine ; Garcia, Marcel ; Maynadier, Marie ; El Cheikh, Khaled ; Godefroy, Anastasia ; Charbonné, Henry-Vincent ; Pau, Bernard ; Morère, Alain ; Perez, Marc ; Daurat, Morgane ; Da Silva, Afitz ; Gary-Bobo, Magali ; Harmois, Alice

Pompe disease is a rare disorder due to deficiency of the acid α-glucosidase (GAA) treated by enzyme replacement therapy. The present authorized treatment with rhGAA, the recombinant human enzyme, provides an important benefit in the infantile onset; however, the juvenile and adult forms of the disease corresponding to >80% of the patients are less responsive to this treatment. This resistance has been mainly attributed to an insufficiency of mannose 6-phosphate residues in rhGAA to address lysosomes through the cation-independent mannose 6-phosphate receptor (CI-M6PR). As yet, several attempts to improve the enzyme delivery by increasing the number of mannose 6-phosphate on the enzyme were poorly effective on the late onset form of the disease. Here, we show that chemical conjugation of a synthetic analogue of the mannose 6-phosphate, named AMFA, onto rhGAA improves the affinity for CI-M6PR and the uptake of the enzyme in fibroblasts and myoblasts of adult Pompe patients. More importantly, only the conjugated rhGAA-AMFA was effective in aged Pompe mice when compared to rhGAA. Weekly treatment with 5-20mg·kg^-1 rhGAA-AMFA provided major improvements of the motor function and of the myofiber structure, whereas rhGAA was inactive. Finally, AMFA addition did not induce supplementary immune response to the enzyme. This modified enzyme, displaying a muscle recovery in aged Pompe mice that was never attained before, could be considered as a potential therapy for the late onset Pompe disease.

100 项与 AMFA-mAbs(NanoMedSyn) 相关的药物交易

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