Rituximab, a prototypic anti-CD20 mAb, and the third-generation anti-CD20 mAb obinutuzumab differ in their ability to activate the complement system. According to recent studies, this contrast stems from the architecture of the antigen–antibody complex formed by these two mAbs that facilitates (rituximab) or disables (obinutuzumab) further oligomerization, leading to engagement of the initial classical complement pathway component C1q. We examined whether a gain-of-function C2 variant that acts downstream of C1q and enforces the formation of complement convertase resistant to physiological decay can impact complement activation by obinutuzumab. Co-application of the C2 variant with obinutuzumab and human serum resulted in complement-dependent cytotoxicity equal to or higher than attainable for rituximab. This effect was observed either in serum or hirudin-anticoagulated whole blood. Long-term (24 h) overall cytotoxicity of obinutuzumab was improved in target cells of moderate sensitivity to complement but diminished in cells of low sensitivity. Our results demonstrate that the ability of complement activation of a given antibody is not ultimately determined at the stage of initial interactions with its target antigen but is modulable at later stages of the cascade and that the benefit of the acquisition of this new effector mechanism by obinutuzumab depends on the target cell characteristics.
利妥昔单抗作为典型的抗CD20单克隆抗体，与第三代抗CD20单抗奥滨尤妥珠单抗在激活补体系统能力方面存在差异。最新研究表明，这种差异源于两种单抗形成的抗原-抗体复合物结构：利妥昔单抗促进后续寡聚化，而奥滨尤妥珠单抗则抑制该过程，从而影响经典补体途径起始组分C1q的募集。本研究探讨了位于C1q下游的功能获得性C2变异体——该变异体能强制形成抵抗生理性衰变的补体转化酶——是否能够影响奥滨尤妥珠单抗的补体激活效能。实验显示，将C2变异体与奥滨尤妥珠单抗及人血清联合应用时，可产生等同于或高于利妥昔单抗的补体依赖性细胞毒性效应。该现象在血清体系及水蛭素抗凝全血体系中均得到验证。在中等补体敏感性的靶细胞中，奥滨尤妥珠单抗的长期（24小时）总体细胞毒性得到提升，而在低敏感性细胞中则出现减弱。本研究结果表明：特定抗体的补体激活能力并非完全取决于其与靶抗原的初始相互作用阶段，而是可通过级联反应后期阶段进行调控；同时奥滨尤妥珠单抗获得这种新效应机制的效益取决于靶细胞特性。
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