Looney Cary M, Schroeder Aaron, Tavares Erica, Garg Jay, Schindler Thomas, Vincenti Flavio, Redfield Robert R, Jordan Stanley C, Busque Stephan, Woodle E Steve, Khan Jared, Eastham Jeffrey, Micallef Sandrine, Austin Cary D, Morimoto Alyssa
Division of Investigative and Immuno Safety, F Hoffmann-La Roche, Basel, Switzerland.
Biomarker Development, Genentech, Inc, South San Francisco, CA.
Transplant Direct. 2023 Jan 19;9(2):e1436. doi: 10.1097/TXD.0000000000001436. eCollection 2023 Feb.
The THEORY study evaluated the effects of single and multiple doses of obinutuzumab, a type 2 anti-CD20 antibody that induces antibody-dependent cell-mediated cytotoxicity and direct cell death, in combination with standard of care in patients with end-stage renal disease.
We measured B-cell subsets and protein biomarkers of B-cell activity in peripheral blood before and after obinutuzumab administration in THEORY patients, and B-cell subsets in lymph nodes in THEORY patients and an untreated comparator cohort.
Obinutuzumab treatment resulted in a rapid loss of B-cell subsets (including naive B, memory B, double-negative, immunoglobulin D transitional cells, and plasmablasts/plasma cells) in peripheral blood and tissue. This loss of B cells was associated with increased B cell-activating factor and decreased CXCL13 levels in circulation.
Our data further characterize the mechanistic profile of obinutuzumab and suggest that it may elicit greater efficacy in indications such as lupus where B-cell targeting therapeutics are limited by the resistance of pathogenic tissue B cells to depletion.
THEORY研究评估了单剂量和多剂量奥滨尤妥珠单抗（一种诱导抗体依赖性细胞介导的细胞毒性和直接细胞死亡的2型抗CD20抗体）与终末期肾病患者的标准治疗联合使用的效果。
我们在THEORY研究患者中测量了奥滨尤妥珠单抗给药前后外周血中的B细胞亚群和B细胞活性的蛋白质生物标志物，以及THEORY研究患者和未治疗的对照队列淋巴结中的B细胞亚群。
奥滨尤妥珠单抗治疗导致外周血和组织中B细胞亚群（包括幼稚B细胞、记忆B细胞、双阴性细胞、免疫球蛋白D过渡细胞和成浆细胞/浆细胞）迅速减少。B细胞的这种减少与循环中B细胞活化因子增加和CXCL13水平降低有关。
我们的数据进一步描述了奥滨尤妥珠单抗的作用机制，表明它可能在诸如狼疮等适应症中发挥更大疗效，在这些适应症中，B细胞靶向治疗因致病性组织B细胞对耗竭的抗性而受到限制。
