Bispecific antibodies targeting PD-1 and CTLA-4: new kids on the block(ade)

Several clinical trials have showed that combining an anti-CTLA-4 inhibitor and an anti-PD-(L)1 inhibitor increases the overall response compared with an anti-PD-(L)1 inhibitor alone. Bispecific antibodies could be a new way to simultaneously block CTLA-4 and PD-1.

Until now, 2 types of immune checkpoint inhibitors have shown clinical effectivity against a broad range of tumours: anti-CTLA-4 inhibitors (e.g. ipilimumab and tremelimumab) and PD-(L)1 inhibitors (e.g. nivolumab, pembrolizumab, atezolizumab, avelumab). There is a rationale to combine these types of immune checkpoint inhibitors because anti-CTLA-4 inhibitors increase the expression of PD-L1 in some tumours and the combination of anti-CTLA-4 inhibition and PD-(L)1 inhibition favours effector T cell recruitment in preclinical tumour models [1]. In addition, several clinical trials have shown that combining an anti-CTLA-4 inhibitor and an anti-PD-(L)1 inhibitor increases the overall response compared with an anti-PD-(L)1 inhibitor alone [2]. However, the combination also induces more serious adverse events (grade ≥3).

Both MGD019 and AK104 are bispecific, tetravalent antibodies targeting both CTLA-4 and PD-1. This makes these molecules potential new candidates to simultaneously block CTLA-4 and PD-L1, hence mimicking the clinical effect of a dual immune checkpoint blockade with e.g. nivolumab plus ipilimumab. In a phase 1, first-in-human, open-label, dose-escalation study, 33 patients with advanced solid tumours were treated with MGD019 in dose escalation from 0.03 to 10 mg/kg [3].

Treatment-related adverse events occurred in 26 of 33 (78.8%) patients, most commonly fatigue (24%), nausea, arthralgia, pruritus, and rash (18% each). The rate of grade ≥3 treatment-related adverse events was 24.2%. Among 25 response-evaluable patients, 4 objective responses were observed also in tumour types that are typically not responsive to checkpoint blockade; 9 patients had stable disease. A phase 2 monotherapy in select expansion cohorts is forthcoming.

In addition, a clinical phase 1 trial with AK104 in 18 patients with mesothelioma, showed 3 out of 18 patients (16.7%) with a grade 3/4 treatment-related adverse event and another 9 subjects experienced grade 1/2 treatment-related adverse events [4]. Confirmed objective response rate was 20%, with a disease control rate of 80%. Median progression-free survival (PFS) was 5.6 months; median PFS in patients who received AK104 in a dose of 4 mg/kg or more (n=16) was 12.9 months.

1. Shi LZ, et al. Nat Commun. 2016; 7:12335.
2. Yang Y, e al. Front Pharmacol. 2020; 11: 40.
3. Sharma M, et al. A phase I, first-in-human, open-label, dose escalation study of MGD019, an investigational bispecific PD-1 x CTLA-4 DART® molecule in patients with advanced solid tumours. ESMO 2020 Virtual Meeting, abstract 1020O.
4. Millward M, et al. Safety and antitumor activity of AK104, a bispecific antibody targeting PD-1 and CTLA-4, in patients with mesothelioma which is relapsed or refractory to standard therapies. ESMO 2020 Virtual Meeting, abstract 1021O.