CD47 is a target of interest and researchers are still trying to figure out what is the best way to target this pathway. Several anti-CD47 targeting agents have been developed and tested in many preclinical and clinical trials over a long-time scale. Such targeting successfully modulates both innate and acquired immune responses against tumor cells [
79]. Despite promising results from most of these studies on the impact of anti-CD47 agents, challenges were found to be in selectivity, efficacy, and safety profile. Recent studies are trying to alleviate these challenges proving that CD47 targeting is a novel anti-cancer approach [
80].
Specificity of anti-CD47 targeting agents
To minimize or avoid cross-reactivity and damage of normal cells due non-selectivity of anti-CD47 agents while exerting anti-cancer effects is a challenge that requires consideration while designing future anti-CD47 therapies [
81]. Ho et al. produced high-affinity CD47-ectodomain antagonist to increase the antibody-dependent phagocytosis [
82]. Moreover, Sim and colleges [
83] discovered high-affinity pan-mammalian and pan-allelic antibodies against SIRPα. Given that older erythrocytes are more susceptible to phagocytosis, future studies of CD47-SIRPα targeting should consider patient age [
84].
Fusion proteins such as SIRPα-IG1 Fc (TTI-621) was developed to avoid damage to normal cells by fusion of the
N-terminal V domain of human SIRPα to the human IgG1 Fc region. At low therapeutic levels, it showed minimal binding affinity to human erythrocytes while exerting enough tumor binding [
55].
Furthermore, combination therapies were developed to achieve increased tumor specificity and decreased toxicity to CD47-expressing non-malignant cells. For example, anti-CD47 antibodies (BRIC126 or B6H12) combined with anti-CD20 rituximab resulted in NHL ablation in xenograft models [
32,
78]. Enhancement of the anti-tumor effects of high-affinity SIRPα-CD47 antibodies obtained when combined with tumor-specific antibodies [
85]. Anti-SIRPα antagonists have also been combined with tumor-opsonizing antibodies such as rituximab showed anti-tumor efficacy in vitro [
82] and in xenograft lymphoma and colon cancer models [
86]. Similarly, targeting CD47 and PD-L1 [
75,
76].
The development of BsAb improved the specificity and reduced the cytotoxicity of anti-CD47 agents. NI-1701, a BsAb that targets CD47 and CD19 was designed for B-cell lymphoma and refractory leukemia [
61]. Other bispecific agents (LicMABs) have been produced by the binding domain of SIRPα to a tumor-targeting antibody such as anti-CD33 promoted elimination of AML tumor cells [
67].
Novel methods for specific targeting CD47 and its ligands on tumor cells have been proved in recent studies. These included drug delivery vehicles such as CD47-conjugated nanoparticles [
87] or quorum-sensing bacteria [
88]. Such delivery resulted in T cell and macrophage induced phagocytosis of tumor cells by blocking CD47 and reduced tumor progression [
87,
88]. Other nanoparticles as magnetic iron oxide have been developed as vehicles for selective simultaneous delivery of anti-CD47 antibodies and gemcitabine for the treatment of pancreatic cancer without cytotoxicity [
89]. Mitomycin A-loaded nanoparticles showed downregulation of CD47 expression in xenografted mice [
90]. Davis et al. combined anti-CD47 antibodies with nanoparticles to target ovarian cancer cells [
91]. No update information about using such vehicles in targeting CD47 in hematological malignancies.
Efficacy of anti-CD47 targeting agents
The potency and the therapeutic effects of anti-CD47 agents varied between different studies according to the type of cancer, type of antibodies, stage of tumor, type of tumor model, drug pharmacokinetics, acquired drug resistanc,e and the state of the immune system [
80]. Drug resistance and unsatisfactory results were in most cases related to tumor heterogeneity, tumor microenvironment changes, drug inactivation, decreased drug absorption, and epigenetic changes [
92].
Toxicity and safety profile of anti-CD47 targeting agents
Given that CD47 is ubiquitously expressed by normal of the hematopoietic system [
93] such as RBCs [
94] and platelets [
95], potential adverse events using anti-CD47 antibodies as cancer therapeutics include anemia and thrombocytopenia. Buatois et al. [
61] showed that Hu47F9-G4 alone or in combination with other antibodies may cause accidental killing of normal hematopoietic cells. To alleviate this adverse effect, one study [
34] proposed to give short priming low-dose of Hu5F9-G4 in combination with rituximab to selectively eliminate the aged red blood cells, followed by long-term treatment. The toxicity of anti-CD47 antibodies is proved to be Fc-dependent; SIRPα-Fc fusion proteins give this toxicity while high-affinity SIRPα generations don’t [
85,
96,
97]. These high-affinity variants bind to CD47 with a greater potency compared with wild type SIRPα [
85]. They showed regression of solid tumors and hematologic malignancies in preclinical trials but not yet in clinical trials [
85,
98].