Targeting Attenuated Interferon-α to Myeloma Cells with a CD38 Antibody Induces Potent Tumor Regression with Reduced Off-Target Activity.
Targeting Attenuated Interferon-α to Myeloma Cells with a CD38 Antibody Induces Potent Tumor Regression with Reduced Off-Target Activity.
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DOI：
10.1371/journal.pone.0162472
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Wilson DS
中科院分区：
文献类型：
--
作者：
Pogue SL;Taura T;Bi M;Yun Y;Sho A;Mikesell G;Behrens C;Sokolovsky M;Hallak H;Rosenstock M;Sanchez E;Chen H;Berenson J;Doyle A;Nock S;Wilson DS
几十年来，干扰素-α (IFNα) 一直被用于有效治疗多发性骨髓瘤 (MM) 和其他恶性肿瘤。然而，由于显着的毒性和狭窄的治疗指数（TI），近年来其使用逐渐减少。我们试图通过以下方法改善 IFNα 的 TI：首先，将其附着到抗 CD38 抗体上，从而将其直接靶向 MM 细胞；其次，通过在融合蛋白的 IFNα 部分中引入减毒突变，使其在正常 CD38 阴性细胞上相对失活。与天然 IFNα 相比，这种抗 CD38-IFNα（减毒）免疫细胞因子或 CD38-Attenukine™ 在体外对 CD38 阳性细胞的特异性提高了 10,000 倍，并且显着的是，在体外对正常骨髓细胞的毒性比天然 IFNα 低约 6,000 倍。此外，减毒突变显着降低了食蟹猴中 IFNα 生物标志物的活性，表明这种方法可能比天然 IFNα 或非减毒 IFNα 免疫细胞因子在人类中产生更好的安全性。在人类异种移植 MM 肿瘤模型中，抗 CD38-IFNα（减毒）在小鼠体内发挥有效的抗肿瘤活性，在大多数情况下诱导肿瘤完全消退。此外，抗 CD38-IFNα（减毒）比标准 MM 治疗（来那度胺、硼替佐米、地塞米松）更有效，并且在异种移植模型中与来那度胺和硼替佐米表现出强大的协同作用。我们的研究结果表明，针对肿瘤的减毒细胞因子（例如 IFNα）可以促进强大的肿瘤杀伤作用，同时最大限度地减少全身毒性。
Interferon-α (IFNα) has been prescribed to effectively treat multiple myeloma (MM) and other malignancies for decades. Its use has waned in recent years, however, due to significant toxicity and a narrow therapeutic index (TI). We sought to improve IFNα’s TI by, first, attaching it to an anti-CD38 antibody, thereby directly targeting it to MM cells, and, second, by introducing an attenuating mutation into the IFNα portion of the fusion protein rendering it relatively inactive on normal, CD38 negative cells. This anti-CD38-IFNα(attenuated) immunocytokine, or CD38-Attenukine™, exhibits 10,000-fold increased specificity for CD38 positive cells in vitro compared to native IFNα and, significantly, is ~6,000-fold less toxic to normal bone marrow cells in vitro than native IFNα. Moreover, the attenuating mutation significantly decreases IFNα biomarker activity in cynomolgus macaques indicating that this approach may yield a better safety profile in humans than native IFNα or a non-attenuated IFNα immunocytokine. In human xenograft MM tumor models, anti-CD38-IFNα(attenuated) exerts potent anti-tumor activity in mice, inducing complete tumor regression in most cases. Furthermore, anti-CD38-IFNα(attenuated) is more efficacious than standard MM treatments (lenalidomide, bortezomib, dexamethasone) and exhibits strong synergy with lenalidomide and with bortezomib in xenograft models. Our findings suggest that tumor-targeted attenuated cytokines such as IFNα can promote robust tumor killing while minimizing systemic toxicity.
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影响因子：
--
作者：
Campbell, Richard A;Berenson, James R
通讯作者：
Berenson, James R
DOI：
10.1124/jpet.102.037002
发表时间：
2002-11-01
影响因子：
3.5
作者：
Osborn, BL;Olsen, HS;Sung, C
通讯作者：
Sung, C
影响因子：
4.4
作者：
Huang, Tzu-Hsuan;Chintalacharuvu, Koteswara R.;Morrison, Sherie L.
通讯作者：
Morrison, Sherie L.
影响因子：
50.5
作者：
Fritz, E;Ludwig, H
通讯作者：
Ludwig, H
影响因子：
4.1
作者：
McLaughlin, F;Mackintosh, J;Farrow, SN
通讯作者：
Farrow, SN