The layout of bispecific antibodies in the field of tumors has become mature, but in the field of autoimmune diseases, the layout of bispecific antibodies is relatively small. The first batch of enlightened MNCs have begun to take action.

Recently, autoimmune bispecific antibody therapy has increasingly become the focus of new drug research and development. Many pharmaceutical giants such as Johnson & Johnson, Sanofi, and Roche have chosen to deploy in the field of autoimmune bispecific antibodies, with a total of more than US$8.15 billion (approximately RMB 59.1 billion) in mergers and acquisitions and related drug transactions.

The track of autoimmune bispecific antibody therapy has changed.

Sanofi, Merck, and Roche: Grabbing the beachhead

of CD3 bispecific antibodiesCD3 is closely related to the activation of T cells. By combining CD3 and tumor-associated antigens, it can guide and activate T cells to approach and kill tumor cells. At present, most of the bispecific antibodies approved for marketing worldwide are TCE bispecific antibodies based on CD3 targets, and their indications include hematological tumors and solid tumors. Today, CD3 bispecific antibodies are expanding to the field of autoimmune diseases, and MNCs are actively deploying.

In July this year, IGM Biosciences announced that it would once again focus on cooperation with Sanofi and transfer all rights and interests of its autoimmune therapies to Sanofi. As early as 2022, IGM Biosciences has reached a cooperation with Sanofi with a down payment of US$150 million and a total price of up to US$6 billion. Sanofi will use IGM Biosciences' unique antibody technology platform to develop agonists for three oncology targets and three immunology/inflammatory targets.

The IGM antibody technology platform has constructed multiple CD3 bispecific antibodies, including: CD3/CD20 bispecific Imvotamab, which is currently undergoing phase 1 clinical exploration for systemic lupus erythematosus, rheumatoid arthritis, and muscle inflammation; CD3/CD38 bispecific IGM-2644, which is currently undergoing a phase 1 clinical trial for systemic myasthenia gravis.

Coincidentally, in August this year, Merck announced the introduction of global rights to Tongrun Bio's CD3/CD19 bispecific CN201. Merck paid a $700 million advance payment and will pay a $600 million milestone payment later. Currently, CN201 is conducting clinical trials for hematological tumors. In the future, Merck plans to study the therapeutic potential of CN201 in the field of autoimmunity.

Roche has a strong bispecific antibody lineup, but it mainly focuses on the fields of blood, tumors and ophthalmology. It is worth noting that in the 2024 Pharmaceutical Research and Development Day report, Roche disclosed two autoimmune bispecific antibody pipelines under development, namely CD3/CD19 bispecific antibody RG6382 and CD3/CD20 bispecific antibody RG7828 (Lunsumio), which are used to treat systemic lupus erythematosus. Currently, the two drugs are undergoing Phase 1 clinical trials.

It can be seen that CD3 bispecific antibodies have become a new battlefield that MNC must win in the field of autoimmune diseases. If they can be successfully verified in the future, CD3 bispecific antibodies will become a potential drug across the three major disease markets of solid tumors, hematological tumors and autoimmune diseases.

Sanofi, Pfizer: TSLP bispecific antibodies are gradually gaining momentum

TSLP (thymic stromal lymphopoietin) is a new type of cytokine similar to IL-7. TSLP is mainly expressed in activated lungs, intestinal epithelial cells, keratinocytes and fibroblasts. Dendritic cells, mast cells and other immune cells can also secrete TSLP. According to literature data, TSLP is associated with a variety of autoimmune diseases such as atopic dermatitis, psoriasis, and rheumatoid arthritis. TSLP

is a verified target. In 2021, Tezepelumab, jointly developed by Amgen and AstraZeneca, was approved for marketing. This is currently the only TSLP monoclonal antibody approved for marketing in the world, used to treat severe asthma. After Tezepelumab was launched, sales rose rapidly, with global sales of US$170 million in 2022 and US$570 million in 2023. Currently, Tezepelumab is expanding its indications to include allergies, chronic spontaneous urticaria, atopic dermatitis, etc. Tezepelumab's

outstanding commercial performance has attracted many MNCs to deploy TSLP targets. The research and development trend mainly focuses on the layout of TSLP dual antibodies and triple antibodies, and many pipelines have entered the mid-to-late clinical stages.

Sanofi's IL-13/TSLP dual antibody Lunsekimig is currently the fastest in research and development. Lunsekimig uses two IL-13 and TSLP nanoantibodies in series to form a multivalent effect, and fuses albumin antibodies to extend the half-life. Currently, Lunsekimig has entered the Phase 2 clinical trial stage for the treatment of asthma and chronic sinusitis with polyps.

Previously, the results of a Phase 1b clinical trial for the treatment of asthma patients showed that compared with the use of IL-13 monoclonal antibody or TSLP monoclonal antibody alone, the exhaled nitric oxide fraction (FeON) of patients treated with Lunsekimig (400 mg dose) was significantly improved. This result shows that the potential synergistic effect of simultaneously inhibiting these two signaling pathways may produce a stronger therapeutic effect.

Lunsekimig is a potential blockbuster therapy that Sanofi has focused on in the field of immunology and inflammation. According to Sanofi's estimates, Lunsekimig's annual sales peak is expected to be 2-5 billion euros.

Another MNC that has deployed TSLP targets is Pfizer. Pfizer's R&D strategy in the field of autoimmunity and inflammation mainly focuses on two aspects:

First, expanding the indications of the marketed product JAK3 inhibitor rituximab. Litaxin has been approved for alopecia areata. Currently, Pfizer is further exploring the therapeutic potential of rituximab in the treatment of vitiligo, ulcerative colitis, Crohn's disease and other diseases.

Second, developing trispecific antibody products. Currently, Pfizer has two trispecific antibodies under development, namely PF-07264660 and PF-07275315. PF-07264660 is a trispecific antibody targeting IL-4/IL-13/IL-33; PF-07275315 is a trispecific antibody targeting IL-4/IL-13/TSLP. Both products under development are used to treat atopic dermatitis and have entered Phase 2 clinical trials.
Johnson & Johnson: Developing dual antibodies to address multiple pathogenic pathways

In the past, Johnson & Johnson's R&D strategy in the field of autoimmunity was mainly focused on developing oral small molecule drugs JNJ-2113 and JNJ-1459 for the two targets of IL-17 and IL-23, and continuously iterating therapies to optimize patients' drug compliance. Now, Johnson & Johnson has begun to expand its territory and deploy a dual-antibody product portfolio to address multiple pathogenic pathways.

In May this year, Johnson & Johnson, which holds five autoimmune ace products, acquired Proteologix, a biotechnology company focusing on bispecific antibodies for immune-mediated diseases, for $850 million.

Proteologix's product pipeline under development includes PX128 and PX130. The former is an IL-13/TSLP bispecific antibody for the treatment of atopic dermatitis and asthma, which is currently in Phase 1 clinical research; the latter is an IL-13/IL-22 bispecific antibody for the treatment of atopic dermatitis, which is currently in the preclinical research stage. This acquisition shows that Johnson & Johnson has created a differentiated and complementary bispecific antibody product portfolio to address multiple pathogenic pathways. Both drugs are designed for a lower frequency of administration, thereby improving the convenience of treatment for patients. Conclusion

In recent years, the field of autoimmunity has made rapid progress, and new targets have emerged in an endless stream. Pharmaceutical giants have expanded their product portfolios and iterated therapies by deploying bispecific antibody pipelines. Among them, bispecific antibody products based on CD3, TSLP, and interleukin series targets, whose drugability has been verified, have become the focus of MNC's new drug research and development. In the future, the field of autoimmune bispecific antibodies is worth looking forward to.

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