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BACKGROUND

Preclinical studies have firmly established the CD47-signal-regulatory protein (SIRP)α axis as a myeloid immune checkpoint in cancer, and this is corroborated by available evidence from the first clinical studies with CD47 blockers. However, CD47 is ubiquitously expressed and mediates functional interactions with other ligands as well, and therefore targeting of the primarily myeloid cell-restricted inhibitory immunoreceptor SIRPα may represent a better strategy.

METHOD

We generated BYON4228, a novel SIRPα-directed antibody. An extensive preclinical characterization was performed, including direct comparisons to previously reported anti-SIRPα antibodies.

RESULTS

BYON4228 is an antibody directed against SIRPα that recognizes both allelic variants of SIRPα in the human population, thereby maximizing its potential clinical applicability. Notably, BYON4228 does not recognize the closely related T-cell expressed SIRPγ that mediates interactions with CD47 as well, which are known to be instrumental in T-cell extravasation and activation. BYON4228 binds to the N-terminal Ig-like domain of SIRPα and its epitope largely overlaps with the CD47-binding site. BYON4228 blocks binding of CD47 to SIRPα and inhibits signaling through the CD47-SIRPα axis. Functional studies show that BYON4228 potentiates macrophage-mediated and neutrophil-mediated killing of hematologic and solid cancer cells in vitro in the presence of a variety of tumor-targeting antibodies, including trastuzumab, rituximab, daratumumab and cetuximab. The silenced Fc region of BYON4228 precludes immune cell-mediated elimination of SIRPα-positive myeloid cells, implying anticipated preservation of myeloid immune effector cells in patients. The unique profile of BYON4228 clearly distinguishes it from previously reported antibodies representative of agents in clinical development, which either lack recognition of one of the two SIRPα polymorphic variants (HEFLB), or cross-react with SIRPγ and inhibit CD47-SIRPγ interactions (SIRPAB-11-K322A, 1H9), and/or have functional Fc regions thereby displaying myeloid cell depletion activity (SIRPAB-11-K322A). In vivo, BYON4228 increases the antitumor activity of rituximab in a B-cell Raji xenograft model in human SIRPα transgenic mice. Finally, BYON4228 shows a favorable safety profile in cynomolgus monkeys.

CONCLUSIONS

Collectively, this defines BYON4228 as a preclinically highly differentiating pan-allelic SIRPα antibody without T-cell SIRPγ recognition that promotes the destruction of antibody-opsonized cancer cells. Clinical studies are planned to start in 2023.

BACKGROUND

METHOD

We generated BYON4228, a novel SIRPα-directed antibody. An extensive preclinical characterization was performed, including direct comparisons to previously reported anti-SIRPα antibodies.

RESULTS

CONCLUSIONS

背景

临床前研究已经明确 CD47-信号调节蛋白（SIRP）α 轴是癌症中的髓系免疫检查点，这与来自首个 CD47 阻断剂临床研究的现有证据相符。然而，CD47 广泛表达，并与其他配体介导功能相互作用，因此靶向主要局限于髓系细胞的抑制性免疫受体 SIRPα 可能是更好的策略。

方法

我们生成了一种新型的 SIRPα 定向抗体 BYON4228。对其进行了广泛的临床前特征分析，包括与之前报道的抗 SIRPα 抗体进行直接比较。

结果

BYON4228 是一种针对 SIRPα 的抗体，可识别人类群体中 SIRPα 的两种等位基因变异体，从而最大限度地提高其潜在的临床适用性。值得注意的是，BYON4228 不识别密切相关的 T 细胞表达的 SIRPγ，该分子介导与 CD47 的相互作用，已知在 T 细胞渗出和激活中起重要作用。BYON4228 与 SIRPα 的 N 端免疫球蛋白样结构域结合，其表位与 CD47 结合位点大部分重叠。BYON4228 阻断 CD47 与 SIRPα 的结合，并抑制 CD47-SIRPα 轴的信号转导。功能研究表明，BYON4228 增强了在各种肿瘤靶向抗体（包括曲妥珠单抗、利妥昔单抗、达雷妥尤单抗和西妥昔单抗）存在下，体外巨噬细胞和中性粒细胞对血液系统和实体癌细胞的杀伤作用。BYON4228 沉默的 Fc 区域排除了免疫细胞介导的 SIRPα 阳性髓系细胞的消除，这意味着预期在患者中保留髓系免疫效应细胞。BYON4228 的独特特征使其明显区别于之前报道的代表临床开发中药物的抗体，这些抗体要么缺乏对两种 SIRPα 多态性变异体之一的识别（HEFLB），要么与 SIRPγ 交叉反应并抑制 CD47-SIRPγ 相互作用（SIRPAB-11-K322A、1H9），且/或具有功能 Fc 区域，从而显示出髓系细胞耗竭活性（SIRPAB-11-K322A）。在体内，BYON4228 增加了 Rituximab 在人 SIRPα 转基因小鼠的 B 细胞 Raji 异种移植模型中的抗肿瘤活性。最后，BYON4228 在食蟹猴中表现出良好的安全性特征。