What exactly is the CD47 that attracts AbbVie to bet on the creatures of heaven and earth?

Overnight, innovative oncology immunotherapy grabbed the headlines again, but this time it was no longer PD-(L)1, but CD47.
September 4th, The Life of Heaven (IMAB. NASDQ and AbbVie have jointly announced an extensive global strategic partnership for the development and commercialization of Tianbi Bio's innovative CD47 single-resistant lemzoprlimab (TJC4), which will receive a total of $1.94 billion in installment milestone payments and a two-digit tiered royalty for future global sales.
this cooperation has become another milestone in China's innovative pharmaceutical industry.
six months ago, Gilead announced a $4.9bn acquisition of Forty-seven, a biotech company focused on developing CD47 path inhibitors.
this is Gilead's larger acquisition of KITe Pharma, a CAR-T therapy research and development company, for $1.2 billion in 2017. The above two high-value acquisitions of
are highly targeted and are important steps for AbbVi and Gilead to switch from autoimmune and viral infections to tumor therapy, respectively, revealing important signals to the global market: cancer immunotherapy targeting the CD47 path is highly promising.
mechanism of the CD47 path, Burnet and Thomas proposed the "immune surveillance" hypothesis that the immune system could monitor and eliminate "foreign" entities to maintain a stable environment, including malignant cells that express various tumor-specific and non-tumor-specific antigens.
monitoring of tumors is an important process to limit tumor growth, macrophages play an important role in identifying and removing tumor cells in the body.
T lymphocytes and NK cells are other important effect cells of the immune system and also play an important role in anti-tumor immunity.
tumor-soaked immune cells, macrophages and T-lymphocytes are the two groups with the highest proportion.
the escape behavior of tumor cells for immune identification and removal depends on several processes, including inducing immunosuppressive tumor microencology and reducing immunogenicity of tumor cells.
mechanism for immune escape of tumor cells is the over-expression of the immunosuppressive signaling molecule CD47.
CD47 is a glycosylated transmean protein present on the surface of many different cell types, the structure includes the extracellular variable region at the amino end, the transmean region formed by the high hydrophobic transmean segment, and the hydrophobic nircotin-based end in the cytoplasm.
of CD47 include SIRP alpha, TSP-1 (plate plate plate reactive protein-1) and the integrator alpha v beta 3 and alpha2 beta1.
SIPR alpha is highly expressed on myelin cell membranes, such as macrophages, granulocytes, monocytes, and myelin dexterous cells, whose extracellular regions contain V-shaped amino ends that bind to CD47.
CD47 is widely regarded as a "don't eat me" signal that helps normal cells maintain immune tolerance under physiological conditions.
However, in many types of cancer, cd47 in cancer cells binds to the signal-regulatory protein α (signal-regulatory protein α) of macrophages, initiating a suppressive signaling path path, so that macrophages no longer devour cancer cells, while anti-CD47 antibodies block inhibition signals and promote phagocytorapy.
(Figure 1) Chart 1. The structure and interaction of CD47 and SIRP alpha indicate ITIM (Tyrosine-based immunoreceptor suppression sequence), SHP-1/2 (protein tyrosine phosphatase substrate-1/2) Source: Front. A large number of studies of anti-tumor therapies targeted at CD47-SIRP alpha pathways at zhongkang Industrial Capital Research Center have shown that CD47 is over-expressed in different types of tumors, including acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic myeloid Leukemia (CML), non-Hodgkin's lymphoma (NHL), myeloma, smooth muscle tumor, osteosarcoma, breast cancer, head and neck squamous cell carcinoma (HNSCC), bladder cancer, lung cancer and hepatocellular carcinoma (HCC).
multiple tumor cell surface over-expression CD47 can help escape the monitoring and removal of immune cells, and expression levels are positively related to disease progress.
widespread expression of CD47 in tumors makes it theoretically possible for drugs with CD47 paths to be used in the treatment of multiple tumors in the same way as PD-(L)1 drugs.
anti-tumor therapy that targets the CD47-SIRP alpha signaling pathrapy can lead to the elimination of tumor cells through a variety of mechanisms.
(Figure 2) (1) Anti-CD47 antibodies, anti-SIRP alpha antibodies, or recombinant SIRP alpha proteins inhibit the interaction of CD47-SIRP alpha, causing macrophages to devour tumor cells.
(2) Anti-CD47 antibody makes dendrites devour tumor cells, and then antigens are presented to CD4 plus and CD8 plus T cells, thus stimulating the adaptive immune response of anti-tumor.
(3) Anti-CD47 antibodies eliminate tumor cells through ADC (antibody-dependent cytotoxicity) and CDC (complement-dependent cytotoxicity) mediated by NK cells (natural killer cells).
(4) anti-CD47 antibody stimulates tumor apoptosis by not relying on the mechanism of cystic winter enzyme (apoptosis protease).
Figure 2. A variety of mechanisms for targeting CD47-SIRP alpha pathways to eliminate tumor cells are sourced from: Curr Opin Immunol., CD47 monoantial TJC4 of Tiantian Biology, China Health Industrial Capital Research Center, mentioned above that normal cells also express CD47, such as normal red blood cells (RBC, redblood cells) and plate plates.
the first wave of anti-CD47 antibodies entering the clinical phase were found in clinical trials to bind to red blood cells, causing serious adverse blood reactions, such as severe anemia.
this defect prevents these CD47 antibodies from being developed as potential tumor therapies.
Tiantian bio-autonomous research and development of cd47-targeted all-human source IgG4 subtype monoantigen lemzoparlimab (TJC4, TJ011133) has a unique antigen binding table, while retaining strong anti-tumor activity, the binding with normal red blood cells is very weak, and does not produce hemagging, can minimize anemia and other adverse reactions caused by antibody injection.
Chart 3. The antigen binding table of TJC4 and its weak action (A) with red blood cells (RBC) are less likely to bind to human red blood cells than for forty Seven's CD47 monoantial 5F9.
(B) TJC4 does not cause clotting.
a single injection at a dose of 20 mg/kg, TJC4 had a smaller effect on the red blood cell count of crab-eating monkeys.
(D) crystal structure analysis of TJC4 antigen binding table.
(E) red blood cells increases binding to TJC4.
source: 2019 ASH, Zhongkang Industrial Capital Research Center TJC4 characteristics are achieved through additional red blood cell anti-screening, screening with CD47 high affinity binding but not binding to red blood cells or minimal binding of rare antibody cloning.
has been fully validated in a series of in vitro and in vivo experiments.
in crab-eating monkey toxicology experiments, TJC4 showed good tolerance at high doses of up to 100 mg/kg of repeated administration, indicating a wide treatment window.
this safety advantage makes TJC4 stand out among its peers around the world and has the potential to be the best-in-class therapy in the world.
2019, TJC4 was approved for FDA clinical trials.
June 2019, TJC4 completed its first phase I clinical study (NCT03934814) in the United States.
This open-label, multi-center, multi-dose, clinical Phase 1 study aims to assess the safety, tolerance, pharmacodynamics (PK), pharmacoetics (PD) and preliminary efficacy of TJC4 monodynamics and in patients with recurring advanced solid and lymphomas (n-88).
The study was carried out in two parts, part 1 included single dose increment (1A), combined Pabli pearl monoantigen (PD-1 monoantigen) dose increment (1B), and Unilitosi monoantigen (CD20 monoantigen) dose increment (1C), and part 2 included a dose extension study.
In September 2019, Tiantian Bio established a clinical partnership with Mercado (MSD) to conduct clinical studies on the combined treatment of TJC4 and Mercado's PD-1 monoantion Keytruda to assess the clinical effectiveness of the combined drug in patients with multiple types of tumors, i.e. Part 1B of the above study.
July 2019, TJC4's clinical trial application (CXSL1900039) was approved by The State Drug Administration of China, which will target patients with advanced malignancies.
April 2020, TJC4 successfully Chinese mainland patients in a clinical phase 1/2a study.
the study was conducted in a multi-center, open-label one-arm clinical trial (NCT04202003) to evaluate the safety, tolerance, PK, PD and initial efficacy of TJC4 single-drug treatment for relapsed/refractic acute myeloid leukemia (AML) and myeloid growth syndrome (MDS).
September 2020, when a strategic cooperation agreement was signed with AbbVie, The preliminary results of the U.S. Phase I clinical study of TJC4 revealed by Tiantian Bio showed its differentiated advantages in safety and better pharmacodynamic properties.
TJC4 single-dose administration from 1 mg/kg to 30 mg/kg dose range showed good tolerance and dose-limiting toxicity (DLT) or severe blood adverse events were not observed in assessable patients.
results will be announced at relevant international academic conferences in the second half of 2020.
Although the results of clinical trials have not yet been published, trials in the raji lymphoma cell transplantation model in NSG mice showed that TJC4 had basically consistent anti-tumor activity at a dose of 10 mg/kg with Forty Seven's 5F9 and mouse-source anti-CD47 monoantigen 2A1.
(Figure 4) Figure 4. Comparison of anti-tumor activity in animal models Source: Company report, Magrolimab Forty Seven's magolimab (5F9) uses IgG4 subtype monoantigen to avoid blood toxicity, and even when combined with red blood cells, its Fc end does not activate macrophages to avoid phagocytosphage.
, magrolimab's association with different red blood cells may cause red blood cell clotting, so the dose needs to be carefully adjusted, leading to stenosis of the treatment window.
therefore, combination therapy is the focus of Forty Seven's follow-up development of magolimab, including monoantigen (Aza cytosine, gysythamide/Osali platinum), monoantigen (PD-L1 monoantitor avelumab, atezolizumab, EGFR monoantiximab, CD20 monoantiximab), and small molecule targeting drug (BTK inhibitor acalabruib).
(Figure 5) Chart 5. Progress in the development of a combination therapy for FORTY Seven's CD47 mono-magrolimab Source: Company Report, Zhongkang Industrial Capital Research Center December 2019, Forty Seven announces the latest clinical advances in magolimab at ASH Annual Meeting for high-risk bone marrow growth In patients with abnormal syndrome (MDS), the total response rate (ORR) was 92% and the total remission rate (CR) was 50%, while in patients with untreated acute myeloid leukemia (AML) suitable for chemotherapy, the total response rate was 64% and the total remission rate was 41%.
solution to adverse blood reactions, innovative therapies for CD47-SIRP alpha pathfours are expected to become another rich new continent in the field of tumor immunity after PD-(L)1.
the global PD-(L)1 drug market in 2019, the cumulative sales of the four PD-(L)1 monodes listed by MSD, BMS, Roche and AstraZeneca alone reached $22.432 billion.
this means that cd47 drugs, with broad-spectrum anti-tumor efficacy similar to those of PD-1 drugs, have a potential market and possibly a size of 20 billion.