iTAbTM Platform (Immunotherapy antibody technology)
iTAbTM Platform (Immunotherapy antibody technology)
Over the past decade, we have been building and optimizing an immunotherapy antibody (iTAbTM) platform with a series of granted patents. The platform applies the mechanism of T-cell engager (TCE) to generate T cell activating bi- or tri-specific iTAb antibody (shown in Figure). One end of the iTAb molecule binds to tumor-associated antigen (TAA), or tumor-specific antigen (TSA) on a tumor target cell, while the other end of the molecule engages T cells. This leads to the activation of T cells and kills the target tumor cells in cancer patients.

Our bi-, tri-specific iTAb drug specifically binds to TAA or TSA on a tumor cell. When engaged with a T cell, it forms an immune synapsis between the tumor cell and the T cell. The T cell is then activated and releases granzymes and perforins leading to tumor cell lysis. An activated T cell becomes a serial tumor cell killer and can also proliferate to enhance the immune functions in patients and to sustain the long-term anti-tumor activities.

The bi-, tri-specific iTAb antibodies have unique properties. The potent T cell-engaging function results in superb targeting-kiling bioactivities. When targeting a TAA, iTAb molecules have 103 – 106-fold potency compared to conventional antibodies. iTAb can kill a tumor cell expressing very low level of TAA, such as tumor stem cells, and a tumor cell expressing a few TSA molecules per cell. An iTAb molecule-lacing Fc fragment avoids the potential off-target toxicities caused by Fc-associated binding, while maintaining the potent T cell engaging property. It also contains a structural stabilizing base designed with an excellent product stability profile and robust manufacturing process, omitting the scale-up requirement during commercial manufacturing.

iTAb Structure and Advantages

iTAbTM: Immunotherapy antibody; TCR: T cell receptor; TAA: Tumor associated antigen; TSA: Tumor specific antigen.
The patent granted iTAb designed structures are shown in the following figure.

The humanized CD3 antibody is cross-reactive to monkey with similar affinity. The iTAb molecule can simultaneously bind two identical antigen epitopes or two different epitopes. It has super tumor-targeting and killing bioactivity with EC50 at fM to pM. It efficiently enters a solid tumor site led to the accumulation of activated infiltrating T cells within the tumor. It also shows a favorable half-life and PK/PD response in monkeys. In the early clinical trials, iTAb shows a much larger safety window with significantly reduced cytokine release. iTAb is produced in CHO cells with robust manufacturing process, with an estimated commercial manufacturing scale at 200 L. iTAb in its liquid formulation shows an excellent stability, as it was within product Specifications after stored at 4℃ for over 3 years.

T Cell Engager (TCE)

An illustration of activated T cells attacking a tumor cell. Once a T cell is engaged with a targeted tumor cell, the T cell is activated leading to the lysis of the tumor cell.
In the 1950s, Burnet and Thomas proposed that tumors express new antigenic potentialities arising from somatic mutation, and that these antigens are specifically targeted by the immune system. Over the past decades, this theory was gradually validated in cancer biology, animal models, and immunotherapy clinical trials. In recent years, immunotherapies have progressed rapidly and brought significant benefits to cancer patients, especially the immunotherapies based on T cell engager (TCE). The mechanism is that the T cell specifically engages the target tumor cell and becomes activated, leading to the target cell lysis. Immunotherapy was awarded as “scientific breakthrough” in journal of Science in 2013.

There are two main technologies for a T cell to engage a target cell: First is Antibody, such as bi-, multi-specific T cell engaging antibodies; second is engineered T cells including CAR-T (chimeric antigen receptor T cell), or TCR-T (T cell receptor T cell) with an engineered T cell receptor. The common features of TCE are that they all take advantages of the potent tumor killing function of T cell in vivo. T cell-engaging antibodies and CAR-T bypass the restriction of MHC, which is a pathway required for a normal T cell activation. Once a T cell is specifically engaged with a target cell, an immune synapsis is formed between the two cells, leading to T cell activation and the release of perforins and granzymes, thus lysing the target cell.

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