Department of Electrical and Computer Engineering , University of Minnesota , Minneapolis , Minnesota 55455 , United States.
Department of Chemistry, Lehigh University , Bethlehem , Pennsylvania 18015 , United States.
Anal Chem. 2018 Nov 6;90(21):12567-12573. doi: 10.1021/acs.analchem.8b02664. Epub 2018 Oct 15.
rHIgM22 is a recombinant human monoclonal IgM designed to promote remyelination, and it is currently in Phase I clinical trials in patients with multiple sclerosis (MS). In animal models of demyelination, a single low dose of rHIgM22 stimulates oligodendrocyte maturation, induces remyelination, preserves axons, and slows the decline of locomotor deficits. Natural autoantibodies like rHIgM22 typically bind to multiple antigens with weak affinity. rHIgM22 binds to oligodendrocytes and myelin. Because the antigens for rHIgM22 is prevalent within and exclusive to central nervous system (CNS) myelin, we used CNS myelin particles in combination with surface plasmon resonance to determine the kinetic and affinity constants for the interaction of rHIgM22 to myelin. We found that both the serum and recombinant forms of the antibody bind to myelin with very small dissociation constants in the 100 pM range, which is highly unusual for natural autoantibodies. The extraordinary affinity between rHIgM22 and myelin may explain why such a low effective dose can stimulate CNS repair in animal models of demyelination and underlie the accumulation of rHIgM22 in the CSF in treated MS patients by targeting myelin.
rHIgM22 是一种重组人源单克隆 IgM，旨在促进髓鞘再生，目前正在多发性硬化症 (MS) 患者的 I 期临床试验中。在脱髓鞘动物模型中，单次低剂量的 rHIgM22 可刺激少突胶质细胞成熟，诱导髓鞘再生，保留轴突，并减缓运动功能缺陷的下降。像 rHIgM22 这样的天然自身抗体通常与多个抗原具有弱亲和力结合。rHIgM22 与少突胶质细胞和髓鞘结合。因为 rHIgM22 的抗原存在于中枢神经系统 (CNS) 髓鞘内且仅限于 CNS 髓鞘，所以我们使用 CNS 髓鞘颗粒与表面等离子体共振相结合来确定 rHIgM22 与髓鞘相互作用的动力学和亲和力常数。我们发现，抗体的血清和重组形式都以非常小的解离常数（在 100 pM 范围内）与髓鞘结合，这对于天然自身抗体来说非常不寻常。rHIgM22 与髓鞘之间的非凡亲和力可能解释了为什么如此低的有效剂量可以在脱髓鞘动物模型中刺激中枢神经系统修复，并通过靶向髓鞘导致 rHIgM22 在治疗后的 MS 患者的 CSF 中积累。
