Overview of TandAb

What is TandAb?

TandAb is a bispecific antibody capable of simultaneously recognizing two different antigens, thus augmenting  the immune system's attack on tumor cells. Comprising two diabodies, each consisting of two distinct chains - a variable light chain region (VL) and a variable heavy chain region (VH) - TandAb is a tetravalent molecule. An advantage of TandAb lies in its efficient expression in E. coli through recombinant DNA technology, without necessitating chemical cross-linking or fusion proteins. Nonetheless, TandAb also has a drawback, displaying  a short half-life that requires continuous infusion or frequent administration. TandAb shows great promise in immune-oncology, with some variants currently undergoing clinical trials or having secured market approval, mainly targeting hematological malignancies and solid tumors. These TandAbs can effectively target antigens on the surface of tumor cells and activation molecules on the surface of immune cells, enabling bridging and killing between the two cell types. However, TandAb faces certain challenges in clinical application, such as toxic side effects, drug resistance, and pharmacokinetics..

Fig.1 The Structures of TandAb Fragments (Bates A, 2019)

TandAb Generation Methods

TandAb can be generated through various methods, such as recombinant DNA technology, chemical cross-linking, and the fusion protein method. Each approach possesses its own advantages and disadvantages, such as expression efficiency, stability, and functionality. Recombinant DNA technology involves manipulating DNA sequences using genetic engineering to produce recombinant proteins in host cells. This method can create TandAb by linking two diabodies in a single chain with a flexible linker. A diabody is composed of two different chains, each containing a VL and a VH from different antibodies arranged head-to-tail. By employing two chains with the same orientation, a bispecific bivalent dimer is produced. A TandAb is composed of two diabodies linked linearly to produce a tetravalent bispecific molecule. Chemical cross-linking, on the other hand, relies on chemical agents to covalently link two or more molecules together. In this method, TandAb can be generated by cross-linking two monoclonal antibodies or antibody fragments with different specificities. The fusion protein method involves genetic engineering to fuse two or more proteins or protein domains together. In this context, TandAb can be generated TandAb by fusing two antibody fragments with different specificities to a common protein scaffold.

TandAb in Cancer Immunotherapy

As a bispecific antibody capable of recognizing two different antigens simultaneously, such as CD3 and tumor-specific antigens, TandAb activate T cells to target and kill tumor cells. TandAb offers significant potential in cancer immunotherapy, particularly in hematological malignancies and solid tumors. Currently, Blinatumomab stands as one approved TandAb used to treat relapsed or refractory B-cell precursor acute lymphoblastic leukemia (B-ALL), and several others s are undergoing clinical trials for various targets and indications.

Hematological malignancies comprise malignant tumors stemming from the abnormal proliferation of the hematopoietic system, including acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), multiple myeloma (MM), Hodgkin lymphoma (HL), non-Hodgkin lymphoma (NHL) among others. TandAb, as a novel type of immunotherapy, effectively harnesses T cells' cytotoxic abilities to eliminate hematological tumor cells. Blinatumomab is presently approved for treating relapsed or refractory B-ALL, while multiple other TandAbs are undergoing clinical trials for different targets and indications.

Solid tumors encompass malignant tumors arising from the abnormal proliferation of solid tissues, such as lung cancer, breast cancer, colorectal cancer, prostate cancer, liver cancer, etc. As a cutting-edge immunotherapy, TandAb utilizes T cells' cytotoxic potential to effectively combat solid tumor cells. Currently, several TandAbs are undergoing clinical trials for different targets and indications in this field.

References

1. Acheampong DO. Bispecific Antibody (bsAb) Construct Formats and their Application in Cancer Therapy. Protein Pept Lett. 2019;26(7):479-493.
2. Bates A, et al. David vs. Goliath: The Structure, Function, and Clinical Prospects of Antibody Fragments. Antibodies (Basel). 2019 Apr 9;8(2):28.
3. Zheng Tian, et al. Bispecific T cell engagers: an emerging therapy for management of hematologic malignancies. Journal of Hematology & Oncology. 2021; 14: 751
4. Shijie Jin, et al. Emerging new therapeutic antibody derivatives for cancer treatment. Signal Transduction and Targeted Therapy. 2022; 7: 392
5. Klaus Günther, et al. RECRUIT-TandAbs: harnessing the immune system to kill cancer cells. Future Oncology. 2012; 8(7): 765-7763
6. Michael Tesar, et al. TandAbs: bispecific antibodies for cancer immunotherapy. Drug Discovery Today. 2016; 21(6): 948-954.
7. Christiane Schewe, et al. TandAbs: Bi-specific Antibodies for Cancer Immunotherapy - Current Status and Future Directions. Antibodies (Basel). 2019; 8(4): 54.
8. Ralf Bargou, et al. Tumor regression in cancer patients by very low doses of a T cell-engaging antibody. Science. 2008; 321(5891): 974-977.
9. Patrick A Baeuerle, et al. Bispecific T-cell engaging antibodies for cancer therapy. Cancer Research. 2009; 69(12): 4941-4944.
10. Jörg U Schmohl, et al. Bispecific T-cell engagers for cancer immunotherapy: current status and future directions. Journal of Nuclear Medicine. 2019; 60(10): 1360-1366.
11. John M Rossi, et al. Engineering bispecific antibodies with defined chain pairing for T-cell immunotherapy of cancer using the DuoBody technology platform. Methods in Molecular Biology (Clifton N.J.). 2020; 2085: 43-58.