Unlike CD47-targeted agents, ES004-B5 exhibits an excellent safety profile in nonhuman primates. ES004-B5 has potential to be an important backbone for SIRPα-based combination therapy and/or bispecific antibodies, which will likely overcome the limitations of CD47-targeted agents encountered in clinical settings.

P1, N=24, Recruiting, Electra Therapeutics Inc. | Phase classification: P1b --> P1 | Trial completion date: Jun 2024 --> Mar 2025 | Trial primary completion date: Mar 2024 --> Dec 2024

To this end, DS-1103a, a newly developed anti-human SIRPα antibody (Ab), was assessed for the potential combination benefit with datopotamab deruxtecan (Dato-DXd) and trastuzumab deruxtecan (T-DXd), DXd-ADCs targeting human trophoblast cell-surface antigen 2 and human epidermal growth factor receptor 2, respectively. Furthermore, in syngeneic mouse models, both Dato-DXd and T-DXd combination with anti-mSIRPα Ab showed stronger anti-tumor activity over the monotherapies. Taken together, this study provides a preclinical rationale of novel therapies for solid tumors combining SIRPα-CD47 blockers with DXd-ADCs.

P1, N=91, Completed, Electra Therapeutics Inc. | Recruiting --> Completed | Trial completion date: Apr 2024 --> Nov 2023 | Trial primary completion date: Apr 2024 --> Nov 2023

We have demonstrated that TNF induces trastuzumab resistance through mucin 4 (MUC4) upregulation and it is an independent biomarker of poor response to therapy in HER2+ breast cancer...TNF blockade was achieved with etanercept (E), which blocks the soluble (sTNF) and transmembrane isoform of TNF, or with the dominant negative protein INB03 (DN) which neutralizes only sTNF...MUC4 is associated with poorly-infiltrated TNBC, and sTNF blockade downregulates its expression decreasing MTS when combined with anti-PD-1. We propose the TNF as a new target for the treatment of TNBC, and MUC4 as a predictive biomarker to guide a combined treatment of TNF blockers with immunotherapy.

P1, N=100, Recruiting, Byondis B.V.

Phase 1 clinical trial design: BYON4228.001 (NCT05737628) is the first-in-human clinical trial of BYON4228, in combination with rituximab, in relapsed or refractory (R/R) B-cell Non-Hodgkin's lymphoma (NHL). Tumor response is determined according to Lugano and LYRIC criteria. An extensive biomarker program in the peripheral blood and bone marrow is included in the trial.

Three patients were refractory to etoposide-based therapies and/or anti-cytokine therapies. Preliminary data suggest ELA026 is well tolerated in sHLH patients and induces early biomarker changes that warrant further clinical investigation.

P1, N=120, Recruiting, Electra Therapeutics Inc. | Trial completion date: Apr 2023 --> Apr 2024 | Trial primary completion date: Apr 2023 --> Apr 2024

P1, N=100, Recruiting, Byondis B.V. | Not yet recruiting --> Recruiting

Here we report: (1) clinical safety, preliminary activity, and pharmacokinetics of GS-0189 as monotherapy and in combination with rituximab from a phase 1 clinical trial in patients with relapsed/refractory NHL (NCT04502706, SRP001); (2) in vitro characterization of GS-0189 binding to SIRPα; and (3) in vitro phagocytic activity. In vitro phagocytosis induced by GS-0189 was also SIRPα variant-dependent. Although clinical development of GS-0189 was discontinued, the CD47-SIRPα signaling pathway remains a promising therapeutic target and should continue to be explored.

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.

Functional studies demonstrate that BYON4228 potentiates both macrophage- and neutrophil-mediated elimination of hematologic and solid cancer cells in vitro in the presence of a variety of tumor targeting antibodies, including rituximab, daratumumab, trastuzumab and cetuximab. Finally, with its impaired Fc-region BYON4228 does not deplete SIRPα+ myeloid cells, in contrast to SIRPAB-11.Thus, BYON4228 differentiates from all three comparator SIRPα mAbs based on at least one fundamental characteristic, thereby underlining its potential to become a best-in-class drug. We therefore endorse its further development for which clinical studies are planned to start in 2023.

High levels of CD11b+SIRPα+ myeloid cells in TME at baseline, but not CD47 tumor expression, correlates with longer survival while MDSC signature in TME at baseline correlates with clinical response. Thus, suggesting that MDSCs expressing SIRPα in TME could represent a predictive efficacy biomarker.

P1, N=100, Not yet recruiting, Byondis B.V.

Hematologic changes were the main TRAEs, and selective SIRPα blockers seemed to have a better grade 1-2 toxicity profile. Treatment was well-tolerated with minimal DLTs.

Lack of SIRPα suppressed lung cancer cell growth in mice, dependent on circulating macrophages and neutrophils, in association with improved phagocytosis and reduced IL-6 expression.

Mechanistically, SIRPA is regulated by its pseudogene, SIRPAP1. Our results suggest a complicated role of SIRPA in the tumor ecosystem, highlighting cell-type-dependent antagonistic effects of the same target on immunotherapy.

Results Our recent work characterized a novel role of tumor SIRPα in suppressing the anti-tumor adaptive immunity. Conclusions SIRPα expression on tumor cells confer resistance to anti-tumor immunity.

Ethics Approval All the in vitro studies employing human blood obtained from healthy volunteers were approved by and conducted in accordance with the guidelines of Daiichi Sankyo Research Ethics Committee. All animal studies were approved by the Institutional Animal Care and Use Committee of Daiichi Sankyo.

Functional studies show that BYON4228 potentiates both macrophage- and neutrophil-mediated elimination of hematologic and solid cancer cells in vitro in the presence of several different tumor targeting antibodies like trastuzumab, rituximab, daratumumab and cetuximab, illustrating the broad potential clinical benefit and application of BYON4228. Clinical studies are planned to start in 2022. Ethics Approval Appropriate ethics approvals were present before commencing studies in vivo.