Bispecific Antibodies Targeting CD3 and CD123

Introduction of CD3

CD3 is an integral component of the T cell receptor (TCR) complex, comprising four polypeptide chains (CD3γ, CD3δ, CD3ε, and CD3ζ) encoded by distinct genes on chromosome 11. Expressed on T cell surfaces, CD3 plays a crucial role in T cell development, activation, proliferation, and differentiation by engaging signal transduction molecules via immunoreceptor tyrosine-based activation motifs (ITAMs). CD3 emerges as a potential target for various immune-related diseases, including autoimmune disorders, transplant rejection, infectious diseases, as well as hematological and solid tumors like acute lymphoblastic leukemia and lymphoma.

Introduction of CD123

CD123 is the alpha subunit of the interleukin-3 receptor (IL-3R), which is encoded by the IL3RA gene on the X chromosome. CD123 forms a heterodimer with the beta subunit (CD131) to constitute a functional IL-3R. CD123 is expressed on various hematopoietic cells, such as hematopoietic stem cells, basophils, plasmacytoid dendritic cells, etc., and regulates their growth, proliferation, survival, and differentiation, by activating signaling pathways such as JAK/STAT, RAS/MAPK, and PI3K. CD123 is overexpressed in many hematological malignancies, such as acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), acute lymphoblastic leukemia (ALL), hairy cell leukemia (HCL), systemic mastocytosis (SM), etc., as well as in some solid tumors, such as ovarian cancer, breast cancer, etc., making it a promising anti-tumor target.

Signaling Pathways Involved in Bispecific Antibodies Targeting CD3 and CD123

The primary mechanism of action for bispecific antibodies (bsAbs) targeting CD3 and CD123 is to induce contact and killing between T cells and CD123-expressing tumor cells, thereby facilitating tumor immunotherapy. Binding simultaneously to CD3 on T cells and CD123 on tumor cells triggers signal transduction within the TCR complex, leading to T cell activation, proliferation, and cytokine secretion. The activation signal is predominantly mediated by ITAMs on the CD3ζ chain, interacting with tyrosine kinases such as ZAP70 and Lck. This activation initiates downstream signaling pathways like JAK/STAT, NF-κB, and MAPK, enhancing T cell effector functions. Additionally, bsAbs inhibit IL-3R signal transduction on tumor cells, impeding their growth and survival. Furthermore, bsAbs deplete IL-3 in the tumor microenvironment, reducing the risk of tumor immune escape.

Clinic Status of Bispecific Antibodies Targeting CD3 and CD123

Several bsAbs targeting CD3 and CD123 are currently undergoing clinical trials, primarily focusing on hematological malignancies such as AML, MDS, and ALL. Notably, JNJ-63709178 has entered phase II clinical trials, while XmAb®14045 and MGD006 are in various stages of phase I clinical trials. Developed by different companies or research institutions, these bsAbs have shown promising safety and efficacy in clinical trials. For instance, JNJ-63709178 exhibited good tolerability and manageable adverse reactions in phase I trials, with observed complete or partial remissions in some AML patients. XmAb®14045 also demonstrated anti-tumor activity and acceptable safety in phase I trials. Table 1 provides key information on the clinical status of bsAbs targeting CD3 and CD123, including targets, developing entities, clinical trial numbers, phases, indications, and populations.

Table 1. Clinical Status of BsAbs Targeting CD3 and CD123

References

1. Kontermann RE, Brinkmann U. Bispecific antibodies. Drug Discov Today. 2015 Jun;20(7):838-47.
2. Spiess C, et al. Alternative molecular formats and therapeutic applications for bispecific antibodies. Mol Immunol. 2015 Oct;67(2 Pt A):95-106.
3. Bacac M, et al. CEA TCB: A novel head-to-tail 2:1 T cell bispecific antibody for treatment of CEA-positive solid tumors. Oncoimmunology. 2016 Sep 2;5(10):e1203498.
4. Labrijn AF, J et al. Bispecific antibodies: a mechanistic review of the pipeline. Nat Rev Drug Discov. 2019 Aug;18(8):585-608.
5. Wang Q, et al. Design and Production of Bispecific Antibodies. Antibodies (Basel). 2019 Aug 2;8(3):43.
6. Wu J, et al. Advances in bispecific antibodies engineering: novel concepts and potential applications. Biomed Res Int. 2015;2015:309304.
7. Chames P, Baty D. Bispecific antibodies for cancer therapy: the light at the end of the tunnel? MAbs. 2009 Nov-Dec;1(6):539-47.
8. Klinger M, et al. Harnessing T cells to fight cancer with BiTE® antibody constructs - past developments and future directions. Immunol Rev. 2016 Jan;270(1):193-208.
9. Frankel SR, Baeuerle PA. Targeting T cells to tumor cells using bispecific antibodies. Curr Opin Chem Biol. 2013 Jun;17(3):385-92.
10. Fan G, et al. Bispecific antibodies and their applications. J Hematol Oncol. 2015 Dec 29;8:130.
11. Stieglmaier J, et al. Novel BiTE antibody constructs for the treatment of acute myeloid leukemia (AML). Leuk Res Rep. 2014 Sep 18;3(2):70-3.
12. Uckun FM, et al. STAT3 is a substrate of SYK tyrosine kinase in B-lineage leukemia/lymphoma cells exposed to oxidative stress. Proc Natl Acad Sci U S A. 2010 Feb 16;107(7):2902-7.