Since 2024, TCE in the field of autoimmune has become completely popular.
Overseas pharmaceutical companies continue to bet on this field, and domestic TCE has also become popular, giving birth to two huge transactions in the history of domestic Biotech going overseas, including Tongrun Bio and Merck reaching an acquisition of CD3/CD19 bispecific antibodies, with a down payment of US$700 million, second only to BMS and Baili Tianheng's cooperation on bispecific ADC; and GSK's acquisition of Enmu Bio's CD3/CD19/CD20 trispecific antibody CMG1A46, with a down payment of US$300 million, which is also at a relatively high level. The popularity of autoimmune TCE is a fact, but it is undeniable that this field is also full of unknowns. On January 10, IGM Biosciences, which transformed from tumor to autoimmunity, suffered a blow: the core pipeline CD20xCD3 bispecific antibody IGM-2323 showed a disappointing depth of B cell depletion in the field of autoimmunity.

IGM had to terminate the development of IGM-2323, and another TCE IGM-2644 was also forced to terminate. The reason is that the two TCEs have the same design concept and both use IgM antibodies. But judging from the performance of IGM-2323, the probability of success may not be high. The news of failure caused IGM's stock price to plummet by nearly 70%, and its market value was only $124 million. IGM's experience will not be a common phenomenon. But to a certain extent, it is like a vane pointing out one thing-this golden track is destined to be a world of ice and fire. While it is hot, stragglers will continue to appear.

Give up tumors and bet on autoimmunity
In the past few years, under the boom of autoimmunity, many biotechs focusing on tumor research and development have turned to the autoimmunity track for various reasons. IGM is just such a company. As a former star tumor biotech, IGM was once glorious, with a market value of more than 6 billion US dollars. However, with unsatisfactory clinical research and parting ways with heavy partners such as Sanofi, it was forced to make a strategic choice.

In December 2023, facing the continuous reduction of cash, IGM began to turn: abandoning the research and development of hematological tumors and entering the field of autoimmunity.
At that time, IGM's two TCEs, CD20xCD3 bispecific antibody IGM-2323 and CD38xCD3 bispecific antibody IGM-2644, were both explored in the field of hematological tumors, the former for non-Hodgkin's lymphoma and the latter for multiple myeloma. But IGM decided to stop the research and development of two TCEs in hematological tumors because of the poor competitive landscape. Of course, this does not mean that IGM completely abandons the tumor pipeline. It also has IgM antibody aplitabart to explore in the field of colorectal cancer.

However, the decision at the end of 2023 does not seem "perfect", and the cash consumption rate is still beyond expectations. At the end of September 2023, the company had a cash balance of $387 million; a year later, at the end of September 2024, it had only $219 million.
Faced with the continued shrinking of cash, in October 2024, IGM hopes to further focus on "focusing on the strategic shift to autoimmune diseases."
This means that the resources of this biotech company will be used for its TCE pipeline in autoimmunity. Among them, CD20 x CD3 dual antibody IGM-2323 has been evaluated in clinical trials for rheumatoid arthritis, systemic lupus erythematosus and myositis, and clinical data are expected to be read out in 2025.
As for CD38 x CD3 dual antibody IGM-2644, it will start clinical trials for systemic myasthenia gravis at the end of 2024.
IGM may also be a microcosm of biotech in the capital winter. Faced with the continued deterioration of cash flow, it can only keep adjusting and adjusting so that it can focus its limited resources on the areas that are most likely to run out.

Ideal is full, reality is skinny
It is not surprising that IGM is betting on autoimmune TCE. As mentioned above, autoimmune TCE has been pursued by the market since last year, and MNCs have flocked to it with a strong willingness to buy, and at the same time, they are willing to pay a high down payment. For IGM, once one of the two TCEs shows positive results in early clinical trials, it is possible to achieve external BD and thus fully revive. And IGM's own technical concept also makes it possible: IGM's antibody research and development ideas are slightly different from those of approved mainstream drugs. Antibodies are divided into immunoglobulin G (IgG) and immunoglobulin M (IgM). In the past 40 years, approved antibodies are mainly IgG type. However, IGM hopes to develop IgM type antibodies. The logic is that IgM antibodies have 10 binding domains, while IgG antibodies have 2, which may lead to a higher total binding ability to target cells.

This higher binding force may bring a series of advantages, such as significantly enhancing cell signaling to kill cancer cells or stimulate T cells, expanding the range of addressable targets, and conquering difficult targets. Its TCE is also built based on the above logic. IGM-2323 fully utilizes the affinity of IgM and the high affinity and high specificity of IgG antibodies by grafting the affinity-matured IgG antibody binding domain onto the polymer framework of IgM antibodies and fusing the single-chain Fv domain that binds CD3 to the J chain.

In IGM's view, IGM-2323 can significantly improve the killing ability of T cells while significantly reducing the cytokine storm (CRS) caused by conventional IgG bispecific antibodies. With better efficacy and higher safety, it will undoubtedly be able to achieve more in the field of autoimmunity. However, ideals are full, but reality is very skinny. On January 10, IGM announced that IGM-2323 had poor efficacy in a Phase Ib study of patients with rheumatoid arthritis and systemic lupus erythematosus.

"The depth and consistency of B cell depletion are not enough to meet our high standards for success," said CEO Mary Beth Harler. Obviously, IGM's antibody research and development ideas are not necessarily correct, at least IGM-2323 failed to make it see the possibility of success. In view of this, IGM also terminated the research and development of IGM-2644, and the road to complete transformation to autoimmunity seems to have encountered difficulties. Affected by the news, the company's stock price fell 66.29% on January 10.

Ice and fire, who will be the next to fall behind
IGM's experience may also fully explain the normal state of innovative drug research and development: a life and death struggle. And this situation will inevitably happen again in the hot TCE autoimmune field.

TCE has been on the road to upgrading. Hematological tumor TCE bispecific antibodies have undergone three iterations. The first-generation TCE bispecific antibody Amgen's BiTE has no half-life, so it uses continuous intravenous infusion and has a large CRS reaction. In order to solve this problem, the second-generation hematological tumor TCE bispecific antibodies basically contain Fc segments, the half-life has been greatly improved, and the front dose administration is used to further reduce the CRS reaction. This also brings higher expectations for hematological tumor TCE bispecific antibodies.

At present, the exploration of technical iterations is still continuing. In order to further reduce CRS, the third-generation hematological tumor TCE bispecific antibody uses a CD3 antibody with lower affinity. Although it remains to be seen whether better results can be achieved, it undoubtedly brings higher hopes.

Overall, there are still many problems that need to be solved for TCE bispecific antibodies, such as improving compliance and assembly efficiency, which is bound to be the focus of the autoimmune market. After all, compared with tumor drugs, autoimmune drugs have more stringent requirements for compliance, safety, etc.
And the hot autoimmune field is not a homogeneous competition. For example, in the GSK large merger case mentioned above, GSK believes that the CMG1A46 molecule design has characteristics: high affinity for CD19 and CD20 positive B cells, low affinity for CD3, which can reduce the toxicity usually associated with TCE. GSK pointed out that preclinical studies have shown that "rapid and deep B cell depletion in blood and tissues may lead to more lasting responses in patients."

For this reason, GSK has high hopes for this molecule, hoping to use CMG1A46 for B cell-driven autoimmune diseases such as systemic lupus erythematosus (SLE) and lupus nephritis (LN), and may be extended to related autoimmune diseases.
However, before it is fully launched, this idea is just an idea, and no one can know how the antibody will behave in the human body. IGM's situation may also serve as a reminder to all players in the TCE autoimmune market.

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