A phase 1 clinical trial of DSP107 alone and in combination with atezolizumab for patients with advanced solid tumors is in the recruitment phase (“type”:”clinical-trial”,”attrs”:”text”:”NCT04440735″,”term_id”:”NCT04440735″NCT04440735). lymphoma. A combination of blockade of the CD47-SIRP axis and secondary targets in the tumor microenvironment (TME) may improve the clinical efficacy of current immunotherapeutic approaches. We evaluated the possible combination and outlined the most promising one. Keywords: CD47, SIRP, immunotherapy, mycosis fungoides, Szary syndrome 1. Introduction CD47 is a marker of self on all normal cells known to regulate cell turnovers, such as cell migration, cytokine production, and T cell activation [1,2,3,4,5,6]. Recently, much interest was attracted to the role of CD47 as a regulator of innate T16Ainh-A01 immune surveillance when bound to a membrane protein called SIRP (SHPS-1/BIT/CD172a) on macrophages and other myeloid cells [7]. Phagocytosis is downregulated when SIRP on a phagocyte binds with CD47 of the target cell [8]. Blocking CD47 makes it unable to restrain SIRP, triggering phagocytosis [8] and creating an attractive therapeutic target. Many hematologic and solid tumors overexpress CD47, including acute and chronic myeloid leukemia (AML and CML) [9], acute lymphoblastic anemia [10], non-Hodgkins lymphoma (NHL) [11], multiple myeloma (MM) [12], and in solid cancers such as bladder, prostate, ovarian, lung, kidney, stomach cancers, hepatocellular carcinoma, gliomas, glioblastoma multiforme [13]. Cutaneous T-cell lymphoma (CTCL) is not an exception; moreover, significant overexpression of CD47 in Szary syndrome [14] and mycosis fungoides [15] makes CTLC an ideal candidate for anti-CD47 therapy. High CD47 expression T16Ainh-A01 in MF correlates with worse outcomes [15]; CTCL tumors with higher CD47 levels have been shown to grow more rapidly and aggressively than their CD47 KO counterparts [15]. Furthermore, being very immunosensitive, CTLC T16Ainh-A01 is a desirable target for biologic therapies, and anti-CD47 is no exception. 2. Anti-CD47-SIRP Agents All biologic agents targeting the CD47-SIRP axis can be divided into five groups: monoclonal antibodies directed against CD47 and SIRP, SIRP proteins, small molecules, and bispecific antibodies (Table 1 and Table 2). Table 1 Anti-CD47 monoclonal antibodies.
CandidateMargolimab (5F9)AO-176Ti-061TJ011133 (TJC4)CC-90002SRF231SHR 1603Fc isotypeIgG4IgG2IgG4IgG4IgG4-PEIgG4IgG4Lead indicationMDS/AML; DLBL; Solid tumors; Colorectal CA; Hematologic malignancies Solid tumors; MM; Preclinical: lymphoma and TLLSolid tumorsR/R solid tumors and lymphomaNot been used as monotherapyR/R NHL in combinationB cell lymphoma, R/R solid tumorsAdvanced CA; hematologic malignancies Open in a separate window Abbreviations: mAb, monoclonal antibody; IgG, immunoglobulin; WT, wild type; CA, cancer; HNSCC, head and neck squamous cell carcinoma; NHL, non-Hodgkin lymphoma; MDS, myelodysplastic syndrome; AML, acute myeloid leukemia; DLBL, diffuse large B-cell lymphoma; NSCLC, non-small cell lung cancer; SCC, squamous cell carcinoma. Table 2 SIRP, SIRP proteins, and bispecific antibodies.
CompanyCelgeneOSE ImmunotherapeuticWeissmans groupALX OncologyTrillium TherapeuticsKahr MedicalWaterstone Hanxbio Pty Ltd. (Wuhan, China) Invent Biologics Shattuck LabsCandidateCC-95251BI 765063 (OSE-172)CV1ALX-148TTI-621TTI-622DSP107HX009IBI322SL-172154MoleculemAbmAb IgG4Truncated SIRP proteinWT SIRP-IgG1 fusion with inactive FcWT SIRP-IgG1 Fc fusionWT SIRP-IgG4 Fc fusionSIRP/41BBCD47/PD1CD47/PDL1SIRP/40LLead indicationSolids tumor, leukemia/lymphomaAdvanced solid tumorsLymphoma; breast CAHNSCC, gastric CA, breast CA, NHL, MDS, AMLHematologic malignanciesNSCLC, SCC, advanced solid tumorsAdvanced solid tumorsNSCLC, cervical, esophageal, and liver CA, HNSCCOvarian CA Open in a separate window Abbreviations: mAb, monoclonal antibody; Ig, immunoglobulin; WT, wild type; CA, cancer; HNSCC, head and neck squamous cell carcinoma; NHL, non-Hodgkin lymphoma; MDS, myelodysplastic syndrome; AML, acute myeloid leukemia; NSCLC, non-small cell lung cancer; SCC, squamous cell carcinoma. 2.1. Anti-CD47 Antibodies Anti-CD47 antibodies endow the FLJ22405 antineoplastic effect in three ways. First, they enable phagocytic uptake of tumor cells by antigen-presenting cells, leading to subsequent antigen presentation to CD4+ and CD8+ T cells, stimulating the anti-tumor adaptive immune response [16]. Second, they eliminate tumor cells via NK cell-mediated antibody-dependent cytotoxicity and complement-dependent cytotoxicity [17]. Third, they stimulate the apoptosis of tumor cells through a caspase-independent mechanism [18]. All the monoclonal antibodies against CD47 have an IgG4 Fc portion, except for AO-176, which contains IgG2 Fc [19]. IgG2 is predominantly responsible for IgG responses against bacterial capsular polysaccharides. Physiologically, IgG2 only significantly binds one Fc receptor, FcRIIa. This offers an advantage of IgG2 over IgG4, as it does not bind to the inhibitory FcRIIB receptor as IgG4 does. However, IgG2 weakly activates complement, while IgG4 does not. This is suboptimal as complement activation in the TME enhances tumor growth and increases T16Ainh-A01 metastasis [20]. IgG2-based anti-CD47 antibodies such as AO-176 may not be as effective as monotherapy. In a phase 1/2 first-in-human study of AO-176, 7/27 (26%) patients with acute myeloid leukemia had stable disease as the best response [21]. IgG4 antibodies (in all other anti-CD47 monoclonal antibodies) bind.