Can Anti-CD47 ācureā cancer?
CD47, a five transmembrane domain, integrin-associated protein that is ubiquitously present throughout the human body. With respect to cancer, CD47 sends a āDonāt eat meā signal to macrophages and therefore considered to be one of the most common mechanisms for aggressive tumor growth. Modulating this signaling pathway has resulted in positive outcomes in almost all cancers studied. (see below)
Dr. Irv Weissman of Stanford Univ. presenting the list of human cancers under study via @CIRMnewsĀ
Hu5F9-G4, the anti-CD47 antibody discovered by Dr. Weissmanās lab and now being developed further by Forty Seven Inc, a spin-off (backed by Google money!). They presented their data from the first-in-human trial in advanced cancers and concluded thatĀ Hu5F9-G4 was well tolerated at 3 mg/kg dosing. However, due to the ubiquitous nature of CD47, antibodies targeting this protein are expected to cause a number of side effects including anemia (RBC loss). To compensate for this adverse effect, they used a priming dose ofĀ Hu5F9-G4 to occupy all RBC CD47 receptors with ālimitedā side effects.
So what about the competition?
Obviously, a number of other biotech companies are also working on therapeutics targeting this pathway. Trillium Therapeutics ($TRIL) remains one of their biggest competitors, and are developing a SIRPαFc and human IgG1 Fc fusion protein (TTI-621) to act as a decoy receptor that elicits phagocytosis by macrophages followed by a T-cell response. They recently presented theĀ resultsĀ from their Phase 1a trail in Diffuse large B-cell lymphoma (DLBCL) and Hodgkinās lymphoma patients (n=6 each). Make what you will of the data (below) but we can all agree it does not look like a ācureā (at least not as a monotherapy in really aggressive cancers). However, it is a start and it would be interesting to see how it works in combination with current drugs targeting antigens - CD20 (rituximab) in B cell lymphomas or HER2 (trastuzumab) in breast cancer.
Curiously, they managed to avoid binding to CD47 on RBCs and claim that this is due to ālack of CD47 membrane mobility combined with moderate affinity of TTI-621 for targetā. However, they observed transient thrombocytopenia in their Phase 1a trial (Data below). Although they downplay this by saying āTTI-621 is generally well toleratedā, they are obviously a little worried about this adverse reaction, hence the development of second generation molecule TTI-622 that, unlike TTI-621, has a human IgG4 Fc fragment. They expect that āTTI-622 is less likely to deplete platelets, enabling higher exposuresā. Ā Ā
Further, they are working on other malignancies including solid tumors with results expected by the end of the year. More recently, they have had one big win by winning against Forty Seven Inc over patent infringement claims (below).Ā
OSE Pharma ($OSE) is taking the obvious alternate approach by blocking the SIRPαFc receptors on macrophages and hence preventing CD47-mediated āDo not eat meā signals. They claim that EFFI-DEM, an IgG4 specifically targetingĀ SIRPαFc has shown promising data in solid tumor preclinical models.Ā
Celgene's CC-90002, anti-CD47 antibody licensed from Inhibrx in 2012 and might be the furthest along in the development process. Data from their Phase 1 trialsĀ expected at the AACR meeting in April this year.Ā
Novimmuneās NI-1701, anti-CD47/CD19 bispecific antibody and NI-1801 anti-CD47/Mesothelin bispecific antibodies are in pre-clinical and discovery phases respectively.Ā
Tioma Therapeutics (formerly Vasculox), a spin-off from William Frazierās lab at Washington Univ., St. Louis. Interestingly, some of his recent papers show additional applications of anti-CD47 antibodies in organ transplants! Ā
Alexo Therapeutics, another Stanford spin-off, are developing āhigh-affinity soluble SIRPα monomers (Alexo compounds)ā to block CD47-SIRPα interaction. These monomers are based on (some very cool) work previously reported from the Garcia lab in collaboration with Dr. Weissman et al.
Edit: I forgot to mention that I am invested in both $TRIL and $CELG stocks.Ā