Bispecific antibodies
tumor, toxicity, neuroendocrine cervical cancer, unresectable cervical cancer, GEN1046
DISEASE PROGRESSION, CERVICAL CANCER, METASTATIC CERVICAL CANCER, TUMOR
Depending on the rapid development of bispecific antibody technologies, there are more and more novel bispecific antibodies targeting two immune checkpoints or one immune checkpoint and one other molecule such as TGF-β. The better anti-tumor efficacy is obtained in preclinical experiments when using bispecific antibodies instead of the mAbs and their combination (Cadonilimab. Cadonilimab (AK104) is a PD-1/CTLA-4 bispecific antibody that had been approved in China to treat patients with relapsed or metastatic cervical cancer who have progressed on or after platinum-based chemotherapy (There are some other ongoing trials of AK104, such as AK104 as a neoadjuvant treatment for IB2-IIA2 cervical cancer (NCT05227651), and a phase II study of AK104 in patients with recurrent or metastatic high-grade neuroendocrine cervical cancer (NCT05063916).GEN1046. GEN1046 is a PD-L1/4-1BB bispecific antibody that has a special mechanism. It can exhibit the conditional 4-1BB agonist activity that relies on the cross-linking with PD-L1. But when playing the role of the PD-L1 inhibitor, it is independent of 4-1BB binding (Besides 4-1BB, other co-stimulatory checkpoints such as ICOS, OX40, and GITR are also being explored in clinical trials. However, the development of their monoclonal antibodies is not going as well as co-inhibitory immune checkpoints. And one of the key points is their potential toxicity (M7824. M7824 (Bintrafusp alfa) is a bifunctional protein composed of an anti-PD-L1 antibody that is fused to the extracellular domain of TGF-β receptor II (functioning as a TGF-β trap) (There are two other ongoing clinical trials about M7824. One is to assess the efficacy and safety of M7824 monotherapy in patients with advanced, unresectable cervical cancer who have disease progression during or after platinum-containing chemotherapy (NCT04246489). The other is to evaluate the safety and tolerability of M7824 in combination with other therapies (cisplatin/carboplatin plus paclitaxel with or without Bevacizumab, cisplatin plus radiotherapy) as the first-line in locally advanced cervical cancer (NCT04551950).SHR-1701. SHR-1701 is a similar bifunctional fusion protein to M7824. In a phase I study of SHR-1701 in 32 recurrent or metastatic cervical cancer, the ORR and DCR were 15.6% (95% CI: 5.3-32.8) and 50.0% (95% CI: 31.9-68.1), respectively. The 6-month duration of response rate was 80.0% (95% CI: 20.4–96.9). There was no difference in ORR between patients with CPS>=1 and CPS<1. And patients with high phosphorylated SMAD2 levels in immune cells or tumor cells had numerically higher ORR (In 2022, a phase III study of SHR-1701 plus paclitaxel and cisplatin/carboplatin with or without Bevacizumab as the first-line treatment in persistent, recurrent, or metastatic cervical cancer had started (NCT05179239).Besides, the quick development of antibody technologies has brought new chances to block or bind more molecules, such as tri-specific antibodies and tetra-specific antibodies. And the tri-specific antibodies have been proven to induce stronger T cell activation and anti-tumor effects 