Targeting the CD47-SIRPα axis continues to show promise in solid tumours

In early-phase studies, two novel agents showed low propensity to induce heamatological toxicities in heavily pre-treated solid tumours Targeting the CD47-SIRPα axis shows potential for promoting antitumour efficacy , as demonstrated earlier this year for two novel CD47-SIRPα-targeting fusion proteins . “However, profound, treatment-limiting cytopenias have been observed with agents investigated so far ( PLoS One. 2019;14:e0218897 ), and represent one of the major hurdles in this emerging research field,” explains Dr Emanuela Romano from Institut Curie, PSL Research University, Paris, France. Specifically designed to have reduced haematological toxicity , two novel CD47-SIRPα-targeting fusion proteins , HCB101 and HCB301 represents a step forward in the field, showing low propensity for inducing cytopenia coupled with deep and durable tumour regression in patients with solid tumours, according to dose-escalation results presented at ESMO TAT Asia 2026 (Hong Kong SAR, China, 12–14 June). In a first study, the maximum tolerated dose was not reached with once-weekly infusions of a SIRPα–IgG4 Fc fusion protein, HCB101, up to 36 mg/kg, and there were two dose-limiting toxicities (grade 3 and grade 4 thrombocytopenia at 2.56 mg/kg and 36 mg/kg doses, respectively), no bleeding events and one grade ≥3 anaemia ( Abstract 63O ). Additionally, there were no cumulative anaemia or febrile neutropenia signals across the dose levels. Preliminary antitumour activity among 67 heavily pre-treated patients with a range of solid tumours included confirmed partial responses in two patients: one with head and neck squamous cell carcinoma (HNSCC) and one with marginal zone lymphoma, which appeared to be consistent with sustained ≥90% occupancy of CD47 receptors at doses ≥8mg/kg. Eleven patients with colorectal cancer, ovarian cancer, HNSCC and sarcoma had stable disease lasting from 4 to ≥9 months. Two dose-limiting toxicities, both grade 4 thrombocytopenia at the 1.2 mg/kg dose level, with no bleeding complications, were reported with the triple checkpoint targeting fusion protein, HCB301 – which targets SIRPα, PD-L1 and TGF-β – in a second study involving 21 heavily pre-treated patients mostly with solid tumours. ( Abstract 64O ). Results were suggestive of disease control at the tested sub-therapeutic doses (0.6–1.2 mg/kg), with best overall response (evaluable in 16 patients) of stable disease in 5 (31%) patients and progressive disease in 9 (56%) patients. Most treatment-associated adverse events (including thrombocytopenia, anaemia, lymphopaenia, hypertension and infusion-related reactions) were grade 1–2, reversible and manageable with standard supportive care. Figure. In heavily pre-treated patients with a range of primarily solid tumours, the triple checkpoint targeting fusion protein, HCB301, showed signals for manageable safety and disease stabilisation (ESMO TAT Asia 2026, Abstract 64O) “Pursuit of novel therapies targeting the CD47-SIRPα axis is an expanding field,” says Romano. For example the bispecific antibody, NI-1801, targeting CD47 and the tumour-associated antigen, mesothelin, has shown encouraging signs of activity and a favourable safety profile when combined with pembrolizumab in heavily pre-treated patients with platinum-resistant, mesothelin-expressing epithelial ovarian cancer ( Ann Oncol. 2025;36(Suppl. 2):S842–S843 ). Also, phase Ib/II clinical trial data for evorpacept, targeting CD47, in combination with the dual HER2-targeting bispecific antibody , zanidatamab, demonstrated activity in 24 patients with HER2-positive metastatic breast cancer with elevated expression of CD47 ( ESMO Breast Cancer 2026;Abstract 72P ). “Several compounds are in development, with varying designs depending on the desired target. The future in this setting is promising, particularly considering the favourable safety profile of these compounds,” Romano concludes.