Siddhi Therapeutics

Immunotherapy has led to important clinical advances in cancer treatment in recent years due to superior cure rates compared with standard therapy. In order to develop a new immunotherapy approach to treating AML, Siddhi Therapeutics proposes to target B7-H3 (CD276), a promising immune checkpoint protein that has been reported to inhibit NK/T cell activation.(1, 2) B7-H3 was also identified as a tumor marker that is overexpressed in several solid tumors(3-7) and hematologic malignancies.(8-10) Recent studies have demonstrated that B7-H3 is overexpressed in AML blasts and that its expression is associated with poor overall survival and event-free survival.(9, 11) B7-H3 belongs to the family of B7 proteins, which are mainly expressed by antigen-presenting cells. B7-H3 is expressed on a variety of cancer cell types, including colon/rectal, pancreatic, stomach, prostate, ovarian, lung, and kidney cancers.(7, 12-15) Furthermore, B7-H3 protects cancer cells from NK cell-mediated lysis, which can be reversed by exposure to an anti–B7-H3 monoclonal antibody (5B14).2(1) These reports suggest that B7-H3 is a novel therapeutic target in AML whose inhibition can sensitize AML cells to immunotherapy.

Siddhi Therapeutics is developing a novel humanized anti-B7-H3 antibody-based therapy to reduce the leukemia burden and improve patient outcomes in acute myeloid leukemia (AML). AML is the most common and aggressive acute leukemia found in adults. An estimated 20,000 people develop AML in the United States every year, and 11,000 die from it. Outcomes remain poor for relapsed/refractory (R/R) AML, with complete remission with/without incomplete hematologic recovery (CR/CRi) rates of 30–35% and a median overall survival of 4–10 months, even with the recent approval of targeted agents such as FLT3 and IDH inhibitors, highlighting the significant unmet need. To address the poor outcomes and limited treatment options for those with AML, Siddhi Therapeutics is developing a novel antibody-based therapy for AML targeting the immune checkpoint protein B7-H3. Data shows that B7-H3 is overexpressed in AML patients and that higher expression levels are associated with poor outcomes. However, though B7-H3-encoding mRNA is widely detectable in many normal human tissues of both lymphoid and non-lymphoid origin, the protein itself is not detectable in these tissues or is present at only low levels. This makes B7-H3 a great therapeutic target in AML. Siddhi Therapeutics’ novel antibody-based therapy for AML targeting the immune checkpoint protein B7-H3 has the potential to improve public health by offering a treatment plan that has the potential to be highly effective, and improve quality, and duration of life.

Recent studies have demonstrated that the disruption of signal regulatory protein alpha (SIRPα)-CD47 interaction results in the preferential phagocytosis of AML cells over normal human hematopoietic cells by macrophages (16, 17). This notion creates a therapeutic opening for agents that disrupt SIRPα-CD47 interactions, which may allow for the preferential clearance of leukemic cells over their normal counterparts.

CD47 has long been known to act as a “marker of self” on red blood cells and platelets, regulating their timely clearance by macrophages (18). It is therefore not surprising that cancer cells have exploited this mechanism of self-recognition to evade immunosurveillance. In line with this notion, elevated expression levels of CD47 constitute an adverse prognostic factor for AML patients. Currently, there are several anti-CD47 monoclonal blocking antibodies that are being tested in clinical trials involving patients with myeloid dysplastic syndrome or AML (19-21). The novel anti-CD47 antibody magrolimab demonstrated significant antileukemic activity when combined with azacitidine for the frontline treatment of AML and myeloid dysplastic syndrome, with high response rates and prolonged survival and duration of response, both in TP53-mutant and wild-type populations (22, 23). In a phase 1b trial of magrolimab with azacytidine in newly diagnosed patients with AML, objective responses were noted in 65% of patients, with negative measurable residual disease in 37% (22, 24).

Because of the relatively restricted tissue expression pattern of SIRPα, SIRPα antagonists may be better tolerated than agents targeting CD47, which is ubiquitously expressed; binds to multiple other ligands, including integrins and thrombospondin; and governs several processes in both normal and malignant tissues. To maximize their utility in enhancing antitumor immunity, SIRPα antagonists must block the interaction of CD47 with SIRPα while minimizing SIRPα signaling. SIRPα consists of an extracellular N-terminal domain composed of 3 immunoglobulin-like domains and a cytoplasmic domain, which has 2 tyrosine phosphorylation sites and 4 immunoreceptor tyrosine inhibitory motifs (25, 26). Binding of CD47 to N-terminal of SIRPα on phagocytic cells induces a phosphorylation reaction of the immunoreceptor tyrosine inhibitory motif (27). This activates protein tyrosine phosphatases Src homology region 2 (SH2) domain-containing phosphatases 1 and 2. Subsequently, dephosphorylation of immunoreceptor tyrosine activation motifs prevents contractile engulfment by the macrophages and sends a “do not eat me” signal to the innate immune system, a new signal that cancers seem to use to evade detection and destruction (17, 28, 29).

FMS-like tyrosine kinase 3 (FLT3) is a transmembrane receptor tyrosine kinase that is normally expressed on hematopoietic stem cells and plays an important role in their differentiation. FLT3 mutations are frequent in AML, occurring in up to 30% of patients.

The most common type of FLT3 mutation is an internal tandem duplication (ITD) (10). Patients with FLT3-ITD-mutated AML have an extremely poor prognosis, with shorter overall survival and higher relapse rates compared to patients who do not carry this mutation (10, 11). Given the importance of FLT3 mutations in disease progression and overall outcomes in AML patients, several targeted therapeutic strategies have been deployed to improve outcomes for patients with FLT3-mutated AML. Tyrosine kinase inhibitors (TKIs) have been extensively investigated in previous and ongoing clinical trials for this subset of AML patients, and the FDA-approved TKIs midostaurin and gilteritinib have been incorporated into the standard treatment regimens (12). However, the bone marrow (BM) microenvironment has been reported to contribute to FLT3 inhibitor resistance, which results in persistence of BM disease (8). Several signaling pathways and downstream targets have been implicated in FLT3-mutated AML disease progression, relapse, and resistance to TKIs. These include but are not limited to PI3K, MAPK, and STAT5 (10, 13). Siddhi Therapeutics is developing small-molecule inhibitors to target FLT3 in AML.


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