Analysis of ADC technology's patent layout strategy

Rongchang Biotech was successfully listed on the Hong Kong stock market in November last year, and recently submitted a prospectus to the Shanghai Stock Exchange to seek a listing on the A-share science and technology innovation board

After analyzing the related patents of Rongchang Biological, the author believes that Rongchang Biological's patent layout strategy is mainly as follows: (1) Layout around core products; (2) According to the pipeline research progress, control the related patent application and publication progress

1.

Figure 1.

1.

As one of the core products, RC18 is a recombinant B lymphocyte stimulating factor (BLyS)/proliferation-inducing ligand (APRIL) dual target fusion protein.

Since then, Rongchang Biological requested the application of the optimized TACI-Fc fusion protein for optic nerve and spinal cord spectrum disease (NMOSD) and multiple sclerosis (MS)

Then, we can see that Rongchang Biologics has laid out preparations of TACI-Fc fusion proteins that optimize the Fc region (WO2021115321A1), and TACI-Fc fusion proteins that optimize the Fc region (WO2021128027A1); among them, the Fc region sequence is optimized to Reduce complement fixation or fixation to reduce complement-dependent cytotoxicity (CDC) effects

1.

RC28 is a VEGF/FGF dual target fusion protein used to treat eye diseases, and it is also one of the core products of Rongchang Biological

As shown in Figure 1, Rongchang Biotechnology protects VEGF/FGF dual target fusion protein 28# (corresponding to RC28) in the basic patent (CN102219859B), which protects VEGF receptor 1, VEGF receptor 2, and FGF receptor A fusion protein composed of the extracellular domain of 1 and human IgG1

In addition, the VEGF-binding fragment of RC28 is derived from the prior art, and the FGF-binding fragment was independently developed by Rongchang Biotech.

1.

RC98 is a new type of PD-L1 monoclonal antibody

2.

Figure 2.
Patent distribution of the antibody-drug conjugate platform, the part in bold is the Linker+drug part of ADC

2.
1 RC48 (Vedicituzumab)

One of the core products, RC48, is a new ADC product independently developed by Rongchang Biotechnology, which is used to treat solid tumors with human epidermal growth factor receptor 2 (HER2) expression (including low expression)
.
In June 2021, RC48 for the treatment of gastric cancer received conditional approval for marketing in China
.

As shown in the figure, the basic patent of RC48 (WO2015074528A1) discloses: HER2 monoclonal antibody-Mc-Vc-PAB linker-MMAE (tubulin inhibitor)
.
Due to the discovery of the outstanding efficacy of RC48 in the treatment of urothelial carcinoma, Rongchang Biotechnology applied for WO2020042941A1
.

Furthermore, Rongchang Biology has deployed RC48 in the diagnosis of the application of Her2 by immunohistochemistry (CN111670201A)
.
At the same time, we can also see that Rongchang Bio is actively deploying the combination of RC48 and chemical drugs (CN112402616A & CN112353947A) to achieve the effect of synergistic treatment of tumors
.

2.
2 RC88

RC88 is a mesothelin (MSLN) targeted ADC for the treatment of MSLN-positive solid tumors
.
The structure of RC88 includes MSLN targeting antibody, cleavable linker and small molecule cytotoxin (MMAE)
.
RC88 uses the innovative bridging technology independently developed by Rongchang Bio to connect antibodies and drugs
.

As shown in Figure 2, the basic application CN107921030A discloses an ADC (MSL-C75) targeting MSLN, which improves the stability of RC88 through autonomous bridging technology
.
However, this patent mainly relates to the optimization of Linker (C75: Py-MAA-Val-Cit-PAB-MMAE), and does not disclose the antibody portion targeting MSLN
.
At the same time, because this application protects the Linker optimization solution, it may also be used to optimize the possibility of other existing pipeline ADC drugs
.

Then, the CN110740754A patent application disclosed the MSLN antibody part, and at the same time protected the Py-MAA-Val-Cit-PAB-MMAE preparation process
.
In addition, Rongchang Biological also applied for a patent application (CN110531077A & CN110531083A) for MSLN immunohistochemical detection using RC88
.

2.
3 RC118

RC118 is an antibody-conjugated drug targeting Claudin 18.
2, which is formed by coupling an anti-human Claudin 18.
2 antibody to the microtubule inhibitor MMAE via a linker
.
Among them, the Claudin 18.
2 antibody part is the Claudin 18.
2 monoclonal antibody introduced by Youhe Pharmaceutical (a subsidiary of Biocytometer), but there is no information related to the ADC drug in the Rongchang Biological Open Patent
.
The author also searched the related patents of Youhe Medicine, but no related antibody patents were found
.

However, as shown in Figure 2, in a patent application CN111433188A on ADC drug linker, the author found that it disclosed ADC targeting Claudin 18.
2, but did not disclose Claudin 18.
2 antibody information
.
However, just like the significance of RC88's patent layout, Rongchang Bio may first protect the ADC drug linker in the linker optimization application
.
Therefore, the linker of the ADC drug disclosed in the patent: Claudin 18.
2-A'-7-VC-PAB-MMAE is probably the linker used by RC118
.

2.
4 RC108

RC108 is an anti-c-Met ADC drug, and no related patent applications have been retrieved yet
.

3.
Bi-anti Hibody platform

Figure 3.
Patent distribution of the bi-anti-Hibody platform

Rongchang Biological's bifunctional antibody platform is called "Hibody", which is said to have superior protein expression and easier to achieve CMC production
.
At present, RC138, RC148 and RC158 in the pipelines that have been published are bi-antibody products, but the relevant targets have not been disclosed
.
As the product information of the double antibody is less disclosed, and there is not much public information on the patent, there is currently only one PCT application related to the double antibody
.
Judging from the claims of the PCT application (WO2021185337A1), the application is more aimed at protecting the dual-antibody platform, listing a large number of combinations of different targets
.
However, the examples are only the three schemes shown in Figure 3: (1) Hib-PDC: the first domain targets PD-1 + the second domain targets CD28, (2) Hib-PDV: first The domain targets PD-1 + the second domain targets VEGF, (3) Hib-PLT: the first domain targets PD-L1 + the second domain targets TGF-β
.
Therefore, the current claims in this case may face considerable challenges in the future review process
.

Among them, Hi-PDC and HI-PDV have the same binding domain of PD-1
.
The application also introduced a Merck patent (WO2015118175A2) similar double antibody as a control, and the three double antibodies of Rongchang Biological have significantly better expression than the control protein
.
In addition, coincidentally, Rongchang Biological disclosed 3 bi-antibody platform pipelines (RC138, RC148 and RC158), and the application just provided three different bi-antibody examples
.
Therefore, the examples in this application may reveal the target information of Rongchang Biological in the double antibody pipeline
.

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