As of now, I personally believe that there are no innovative targets and innovative products that can rewrite the pattern of tumor treatment in the post-PD-1 era. Even with the current hot Claudin18.2 target, previous articles have repeatedly mentioned the hidden concerns contained in this target. The CD47 target, which has been expected more, has been full of ups and downs.
——CD47 Track News——
吉利德丨Magrolimab(CD47单抗)
On February 7, 2024, Gilead announced the termination of the Phase III clinical study of CD47 antibody for the treatment of acute myeloid leukemia (AML), the ENHANCE-3 study. This means that the FDA has suspended the clinical study requirements for all clinical studies of magrolimab for the treatment of AML and MDS.
On July 21, 2023, Gilead will discontinue the Phase III ENRICH study, which explores the efficacy of magrolimab (CD47 antibody) in combination with azacitidine in high-risk myelodysplastic syndrome (MDS). Based on the results of the planned analysis of the ENHANCE study, the study has been discontinued due to invalid study results. The safety data in this study are consistent with the known properties of magrolimab and adverse events typical in this patient population. Gilead recommends discontinuing treatment with magrolimab in patients with MDS.
On September 26, 2023, Gilead announced the discontinuation of the ENHANCE-2 study of magrolimab, a CD47 monoclonal antibody, in TP53-mutant acute myeloid leukemia (AML). Based on an ad hoc analysis and review by an independent data monitoring committee, Gilead believes that magrolimab is unlikely to show a survival benefit compared to standard care in patients with TP53-mutated AML. No new safety signals were found, and safety was comparable between treatment groups.
As early as January 25, 2022, Gilead announced the partial suspension of all clinical studies of CD47 antibody + azacitidine combination therapy.
The reason for the discontinuation of the combination was that the FDA requested that the clinical study of the combination be partially suspended due to a significant imbalance in the investigator's discovery of a significant imbalance in the investigator-reported suspected unexpected serious adverse reactions (SUSARs) in the different trial arms of the Magrolimab + azacitidine combination clinical study.
In summary, with the failure of the three Phase III clinical trials due to non-benefit and increased risk of death, Gilead completely abandoned the exploration of CD47 antibody in hematologic tumors. After Gilead's $4.9 billion cash acquisition of Forty Seven's core asset, Magrolimab, it suffered repeated setbacks in the clinical development of magrolimab, while ALX Oncology, another early mover in CD47, began to turn its attention to solid tumors.
ALX Oncology丨ALX148 (SIRPα V1D1-Fc融合蛋白)
On October 3, 2023, ALX Oncology announced preliminary interim data from the Phase II clinical trial of ALX148 (SIRPα V1D1-Fc fusion protein) ASPEN-06. ASPEN-06 is a randomized, double-blind, multicenter clinical study evaluating ALX Oncology in combination with trastuzumab + CYRAMZA + paclitaxel in the treatment of her2-positive gastric/gastroesophageal junction carcinoma (GEJ).
On October 3, 2023, ALX Oncology (NASDAQ: ALXO), a trailblazer in the CD47 track, announced positive results from the Phase 2 interim data of its ASPEN-06 clinical trial. The trial is a randomized, multicenter, international study evaluating ALX Oncology's CD47 blocker evorpacept (ALX148, SIRPα V1D1-Fc fusion protein) + trastuzumab + CYRAMZA® (ramucirumab) + paclitaxel in combination with HER2-positive gastric/gastroesophageal junction ("GEJ") cancer. This pre-specified interim analysis included the results of 54 patients with second- and third-line gastric/gastroesophageal junction cancers, including a certain number of patients who had previously received ENHERTU (trastuzumab) and immune checkpoint inhibitors®. Patients were treated with evorpacept at 30 mg/kg every two weeks, consistent with the treatment cycle of trastuzumab, CYRAMZA, and paclitaxel.
- Compared to trastuzumab + CYRAMZA + paclitaxel, the evorpacept plus trastuzumab + CYRAMZA+ paclitaxel group showed an overall efficacy response rate (ORR) of 52% compared to 22% in the control group.
- The median sustained response time (mDOR) was not reached in the evorpacept combination group compared to 7.4 months in the control group.
- The safety profile of evorpacept is consistent with previous clinical trials and is well tolerated.
- These interim results were superior to the efficacy reports of CYRAMZA+paclitaxel in the RAINBOW study, which was the standard of care for second-line gastric/gastroesophageal junction cancers (ORR of 28% and mDOR of 4.4 months).
"The ASPEN-06 clinical trial validates the potential of evorpacept in combination with anti-tumor antibodies in the treatment of solid tumors, and these data highlight the potential of this drug as a first-in-class primary immunotherapy," said Sophia Randolph, MD, Chief Medical Officer of ALX Oncology. ”。 "In addition, ASPEN-06 is the first global randomized study of HER2-positive tumors, and the previous KEYTRUDA® (pembrolizumab) and ENHERTU were allowed by regulation. We look forward to reporting the final assays of the ongoing Phase 2 study of ASPEN-06 in the second quarter of 2024 and plan to initiate the Phase III study of ASPEN-06 in late 2024. ”
I suddenly remembered the Keynote811 study, which was a study in the field of gastric cancer, which had been inferior to drug O, and found a new way to bypass Her2-gastric cancer, and chose combination therapy to explore Her2+ gastric cancer, and succeeded. In the era when the winner is king, not to mention what kind of multi-drug combination.
The above is the pipeline of ALX Oncology. The CD47 track, after experiencing many ups and downs, gradually found the right point of force.
On the CD47 track, many domestic companies are still expanding in the field of hematological tumors, with different joys and sorrows.
IMM01 (SIRPαFc fusion protein)
On November 8, 2023, Yiming Angke announced that the FDA has granted orphan drug designation to SIRPαFc fusion protein IMM01 targeting CD47 in combination with azacitican for the treatment of chronic myelomonocytic leukemia (CMML). IMM01, the first STRPa-Fc fusion protein to enter the clinical stage in China, is being developed in combination with other drugs for the treatment of a variety of blood cancers and solid tumors.
In June 2022, Yiming Angke officially launched the Phase II para-column expansion trial of IMM01 in combination with azacitidine, combined with the preliminary data of the Phase I and Phase II clinical trials, due to its dual control and good safety, IMM01 is likely to become the target of combination with azacitidine, which can produce a synergistic tumor killing effect without aggravating blood toxicity. According to public information, Yiming Angke intends to carry out pivotal clinical trials in China in the first quarter of 2024. There are also three CD47-based bispecific molecules IMM0306 (CD47×CD20), IMM2902 (CD47×HER2) and IMM2520 (CD47×PD-L1), the first two of which are world-first bispecific molecules that have entered clinical trials for their respective targets.
I-Mab丨Lemzoparlimab (CD47 Antibody)
On September 22, 2023, I-Mab announced the termination of the CD47 antibody collaboration agreement by AbbVie, which was made by AbbVie based on previous program terminations and strategic adjustments. Effective November 20, I-Mab regains global rights to the CD47 antibody and will not affect I-Mab's US$200 million upfront payment + milestone amount. Lemzoparlimab is currently in Phase III clinical trials in combination with azacitidine for the first-line treatment of high-risk MDS.
On February 7, 2024, I-Mab Biotech (Hangzhou) Co., Ltd. entered into an agreement with NASDAQ-listed I-Mab to integrate and restructure all of I-Mab's China businesses, teams and pipelines with the company's existing pipelines and assets. At the same time, I-Mab Biotech (Hangzhou) Co., Ltd. also announced the completion of a Series C1 financing of over RMB 500 million. This round of financing is jointly invested by Tailong Investment, Heda Health Fund, I-Mab, Hangzhou Qiantang Chengfa Technology Service Co., Ltd., Bruggemoon Limited, and Ningbo Kaitou Hanrun Capital.
To sum up, the investment in innovative drugs must have a certain professional background, and blind investment is the biggest risk. We still need to review the mechanism of action and drug defects of CD47 itself in order to seek suitable product iteration and upgrading.
——CD47 Introduction——
The star target CD47, the research and development process has been twists and turns, and it is also a controversial target, because there is a big gap from theory to practice, and after Celgene Pharmaceuticals suspended relevant trials, CD47 was even more overshadowed. With the acquisition of the leading company Forty Seven by Gilead for $4.9 billion, it has gradually attracted more attention. Large pharmaceutical companies such as Gilead, AbbVie, and Boehringer Ingelheim have successively deployed this target, and the track has gradually become hot again.
| Acquirer | R&D | Price |
| Boehringer Ingelheim | Surface Oncology | $37 million |
| Gilead | Forty Seven | $4.9 billion |
| AbbVie | I-Mab creatures | $1.94 billion |
| Pfizer | Trillium Therapeutics | $25 million |
In the article "Apple in the pharmaceutical industry, the miracle road of Gilled's company", the first brother of antiviral drug research and development, Gilled has introduced that Gillette has introduced the large-scale acquisition of Forty Seven, the leading CD47 leader with the fastest clinical development speed at present, and I believe that it is very optimistic about this track. However, in the process of collecting and collating information, I became more and more aware of why CD47 was so controversial.
CD47 information
| 英文名称：Cluster of Differentiation 47 | Number of drugs on the market: 0 |
| Chinese name: Differentiation group 47 | Number of clinical drugs: 20 |
| 靶点别称：Protein MER6，Integrin-associated protein，Antigenic surface determinant protein OA3，Leukocyte surface antigen CD47，CD47，MER6，CD_antigen: CD47 | Highest R&D stage: Phase III clinical trial |
CD47 signal path
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资料来源：Forty Seven公开资料
CD47, which is highly expressed on tumor cells, can transmit the "don't eat me" signal to macrophages (binding to SIRPα on the surface of macrophages) and defeat the "eat me" signals expressed on tumor cells (such as calreticulin, etc.), thereby shielding the phagocytosis of macrophages. Then, if monoclonal antibodies are used to block the CD47/SIRPα signaling pathway, the phagocytosis of tumor cells by macrophages can be restored, which is of course an ideal state. But once feasible, it can have a broad spectrum of anti-cancer capabilities. So this track has a super attraction.
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The role of CD47 in tumor development and maintenance of red blood cell homeostasis
However, the most unavoidable problem of CD47 target drug is the safety issue, CD47 is also involved in maintaining the balance of red blood cells in the body: CD47 is also expressed on the surface of red blood cells in the body, and on the surface of senescent red blood cells, the expression of CD47 is down-regulated or conformationally changed, the "don't eat me" signal is reduced, and the expression of "eat me" signals such as phosphatidylserine is increased, which promotes the phagocytosis of senescent red blood cells by macrophages. While CD47 treatment drugs kill tumor cells, they will inevitably injure red blood cells.
——Defects in the Theory of Finished Drugs——
This was also confirmed by the results of several trials that were terminated. Anemia and thrombocytopenia have become obstacles to some CD47 candidates under development. Therefore, the core of CD47 drug development is how to maximize the killing of tumor cells while protecting red blood cells, which is why I am skeptical about the so-called tertiary and quadruple antibodies. The human immune system is a very sophisticated system, and the fewer targets it triggers, the lower the side effects it will cause, and the more likely it is to become a drug.
Four anti-tumor mechanisms of CD47-targeted drugs
The mechanism of action mainly includes the four aspects shown in the above figure. Among them, the two core mechanisms of action are: blocking macrophage phagocytosis induced by CD47/SIRPα "don't eat me" signaling, or traditional effector functions caused by the Fc terminus of monoclonal antibodies, such as ADCC (antibody-dependent cell-mediated cytotoxicity) and CDC (complement-dependent cytotoxicity).
The two mechanisms are also a double-edged sword, and if the Fc side causes ADCC and CDC to act too strongly, it will inevitably kill a large number of red blood cells, causing serious toxicity problems. Conversely, if the Fc terminus-mediated effects are completely discarded and only rely on the biological functions exerted by the CD47/SIRPα signaling pathway, it is not sufficient to activate a significant anti-tumor response. This dilemma has brought the development of CD47 drugs to an impasse from the beginning.
The mainstream approach represented by Celgene, Forty Seven, Arch Oncology, and Surface Oncology is to develop CD47 antibodies with IgG4 terminus Fc, rather than IgG1 antibodies that can elicit strong ADCC and CDC effects. Such a strategy will reduce the effect on red blood cells and platelets, but there is a large body of data to prove that replacing IgG1 with IgG4 will greatly reduce the ability of CD47 monoclonal antibody to kill tumor cells.
It is also a foreseeable fact that the safety is improved, but the efficacy of the drug is reduced. Therefore, when the clinical trial protocol strategy is formulated, the combination of CD47 monoclonal antibody with other drugs has become the mainstream regimen. In particular, the combination of targeted drugs that require the phagocytosis of macrophages and natural killer cells and rely on the ADCC effect to exert anti-tumor effects. or PD-1/PD-L1 inhibitors that modulate the immune system. It is natural for us to think that CD47-based bispecific antibodies are also another possible direction of development.
The second solution is to reduce the ability of CD47 drugs to bind to red blood cells, thereby avoiding the killing of red blood cells, which is a strategy used by Trillium. Trillium's product, TTI-621, is a fusion protein consisting of the SIRP protein and the Fc terminus of the antibody, which has only a weak binding capacity to red blood cells (possibly related to the conformational alteration of CD47 on the red blood cell membrane), so a more effective IgG1-type Fc terminus can be used. However, TTI-621 is still able to bind to human platelets and leukocytes, so it may still cause thrombocytopenia or leukopenia.
In addition, the way to improve safety is through the dosing regimen of "low-dose induction + effective dose maintenance", which has a certain effect on reducing the side effects of anemia.
There are many companies with CD47 layout in China, including I-Mab, Innovent Biologics, Yiming Oncore, and Akeso.
Taking the humanized monoclonal antibody (AK117, IgG4 subtype) of CD47 that I have tracked as an example, let's take a look at the engineering transformation technology and corresponding safety data of specific domestic biotech companies in this target.
At the 35th Annual Meeting of the Society for Immunotherapy of Oncology (SITC 2020), Akeso Biopharma (9926. HK) presented the progress of the first-in-human clinical study of the Company's self-developed next-generation humanized monoclonal antibody targeting CD47 (AK117) in the form of a poster presentation, titled "A Phase I Clinical Study to Evaluate the Safety, Pharmacokinetics and Antitumor Activity of the Next-Generation Anti-CD47 Monoclonal Antibody (AK117) in Patients With Relapsed/Refractory Advanced or Metastatic Solid Tumors or Lymphomas".
Dose-escalation clinical trials of AK117 are underway in Australia for patients with advanced solid tumors and lymphomas, and dosing is currently in preparation for the 20mg/kg QW cohort. The AK117 study showed that:
- There were no symptoms of drug-related anemia and no treatment-related grade 3 or above adverse events in the 0.3 mg/kg, 1 mg/kg, and 3 mg/kg cohorts of AK117 and the ongoing 10 mg/kg QW cohorts, so there was no need to use a priming dose;
- The subjects in each cohort tolerated the drug well, and no dose-limiting toxicity (DLT) events occurred.
- The receptor occupancy of CD47 in the subject's peripheral blood T cells reached and maintained 100% in the 3mg/kg QW cohort.
In preclinical studies, AK117 has demonstrated differentiated characteristics from other anti-CD47 antibody drugs while maintaining good antigen-binding activity, pro-phagocytosis activity and anti-tumor pharmacological activity:
- AK117不引起红细胞聚集；
- AK117-mediated macrophage phagocytosis was significantly weaker than tumor cell phagocytosis.
- Compared with the obvious anemia of other CD47 antibodies, AK117 showed only slight red blood cell changes in cynomolgus monkeys, and no toxic effect on platelets was observed.
In July 2021, AK117 completed the phase I dose escalation trial in Australia, and there was no DLT (dose-limiting toxicity) and no clinically significant anemia in the subjects in each dose escalation cohort (0.3mg/kg - 45mg/kg QW), and the subjects in each cohort were well tolerated by the drug and did not need to be administered with low-dose pre-excitation. Obtained approval from the National Medical Products Administration (NMPA) to carry out a phase Ib/II clinical study in combination with azacitidine in the treatment of acute myeloid leukemia (AML).
From theory to practice, there is really a long way to go, and the process of groping in the middle is rugged. CD47 is a quasi-drug-specific target, which requires more elaborate design exploration, and it is especially expected that the CD47 target can solve the toxic side effects, even if the efficacy is reduced, and the possibility of becoming a drug-specific drug can be realized through combination and bispecific antibody technology iteration.