Center for Translational Immunology, UMC Utrecht, Utrecht, The Netherlands.
Department of Pediatric Hemato-oncology, Princess Maxima Center for Pediatric Oncology, Utrecht, The Netherlands.
J Immunother Cancer. 2021 Oct;9(10). doi: 10.1136/jitc-2021-003163.
The addition of monoclonal antibody therapy against GD2 to the treatment of high-risk neuroblastoma led to improved responses in patients. Nevertheless, administration of GD2 antibodies against neuroblastoma is associated with therapy-limiting neuropathic pain. This severe pain is evoked at least partially through complement activation on GD2-expressing sensory neurons.
To reduce pain while maintaining antitumor activity, we have reformatted the approved GD2 antibody ch14.18 into the IgA1 isotype. This novel reformatted IgA is unable to activate the complement system but efficiently activates leukocytes through the FcαRI (CD89).
IgA GD2 did not activate the complement system in vitro nor induced pain in mice. Importantly, neutrophil-mediated killing of neuroblastoma cells is enhanced with IgA in comparison to IgG, resulting in efficient tumoricidal capacity of the antibody in vitro and in vivo.
Our results indicate that employing IgA GD2 as a novel isotype has two major benefits: it halts antibody-induced excruciating pain and improves neutrophil-mediated lysis of neuroblastoma. Thus, we postulate that patients with high-risk neuroblastoma would strongly benefit from IgA GD2 therapy.
针对 GD2 的单克隆抗体疗法在高危神经母细胞瘤的治疗中得到了应用，使患者的反应得到了改善。然而，针对神经母细胞瘤的 GD2 抗体的给药与治疗相关的神经病理性疼痛有关。这种严重的疼痛至少部分是通过表达 GD2 的感觉神经元上的补体激活引起的。
为了在保持抗肿瘤活性的同时减轻疼痛，我们将已批准的 GD2 抗体 ch14.18 改构成 IgA1 同种型。这种新型的重构成分 IgA 不能激活补体系统，但能通过 FcαRI（CD89）有效地激活白细胞。
IgA GD2 在体外既不激活补体系统，也不会在小鼠中引起疼痛。重要的是，与 IgG 相比，IgA 增强了中性粒细胞对神经母细胞瘤细胞的杀伤作用，从而提高了抗体在体外和体内的杀瘤能力。
我们的结果表明，采用 IgA GD2 作为新型同种型具有两大优势：它可以阻止抗体引起的剧痛，并提高中性粒细胞介导的神经母细胞瘤溶解作用。因此，我们推测高危神经母细胞瘤患者将从 IgA GD2 治疗中获益匪浅。
