CD20-TCB

(RG6026)

CD20-TCB, a T-cell bispecific antibody for B-cell malignancies
Breast
  • Phase
  • I
  • II
  • III
Gastrointestinal
  • Phase
  • I
  • II
  • III
Genitourinary
  • Phase
  • I
  • II
  • III
Gynecologic
  • Phase
  • I
  • II
  • III
Hematology
  • Phase
  • I
  • II
  • III
Lung
  • Phase
  • I
  • II
  • III
Melanoma
  • Phase
  • I
  • II
  • III
Solid Tumor
  • Phase
  • I
  • II
  • III

This compound and its uses are investigational and have not been approved by the US Food and Drug Administration. Efficacy and safety have not been established. The information presented should not be construed as a recommendation for use. The relevance of findings in preclinical studies to humans is currently being evaluated.

CD20/CD3-targeting bispecific antibody for B-cell malignancies

CD20-TCB (also known as RO7082859, RG6026) is an investigational, full-length, CD20/CD3 bispecific antibody that is developed to redirect T cells to engage and eliminate malignant B cells.1-4 CD20-TCB is designed to bind to CD20, a B-cell surface protein expressed in a majority of B-cell malignancies, while simultaneously binding to CD3, a component of the TCR on the surface of T cells.1,2,5,6 CD20-TCB is equipped with an Fc region that has been engineered to abolish FcγRs and C1q binding while maintaining FcRn binding, which may allow for an extended circulatory half-life.1,2,7 In preclinical models, CD20-TCB demonstrated potent anticancer activity, including T-cell activation, proliferation, and B-cell killing.1,2 Furthermore, CD20-TCB administered with a PD-L1 blocking antibody led to enhanced inhibition of tumor growth in preclinical combination studies.2

 

1 Optimized structure facilitates activity against cancer cells

 

CD20-TCB is an investigational, bispecific antibody with a distinctive design that features 2 Fab arms for binding CD20 on B cells, along with 1 Fab arm for binding CD3 on T cells. The CD3 binding arm is fused directly to one of the CD20 binding arms in a head-to-tail fashion via a short flexible linker. This unique structure allows for high-avidity binding to CD20 that can result in potent activity against B cells even under low effector-to-target (E:T) cell ratios.1,2

CD20-TCB simultaneously binds to CD20 on B cells and to CD3 on T cells

 

2 Developed to direct immune cells to attack and kill cancer cells

 

Upon binding to CD20 on a B cell and CD3 on a T cell, CD20-TCB may induce activation of the T cell and subsequent formation of an immunologic synapse between the two cells.1,2,6 This is followed by secretion of cytotoxic granules, including perforin and granzyme, by the activated T cell. Perforin creates large transmembrane pores on the surface of the bound B cell, allowing granzymes to enter the cell. Granzymes trigger a series of biochemical reactions, resulting in B-cell lysis.8,9

T cells secrete cytotoxic granules, including granzyme and perforin, towards cancer cells

 

3 Potent anticancer effects demonstrated in preclinical studies

 

In preclinical models of multiple B-cell malignancies, CD20-TCB administration led to potent B-cell killing and tumor regression. Preclinical models also suggest CD20-TCB activity leads to the proliferation/expansion of T cells at the site of activation and increased intra-tumor T-cell infiltration.1,2 CD20-TCB continues to be investigated in ongoing clinical trials, including in combination with PD-L1 inhibition, for B-cell malignancies.10

CD20-TCB administration leads to T-cell activation and proliferation and subsequent cancer-cell death

C1q=complement component 1, q subcomponent; CD=cluster of differentiation; Fab=fragment antigen binding; Fc=fragment crystallizable; FcγR=Fc gamma receptor; FcRn=neonatal Fc receptor; PD-L1=programmed death-ligand 1; TCB=T-cell bispecific; TCR=T-cell receptor.

References

  1. Bacac M, Colombetti S, Herter S, et al. Clin Cancer Res. 2018. pii: clincanres.0455.2018. PMID: 29716920
  2. Bacac M, Umaña P, Herter S, et al. Blood. 2016;128:1836.
  3. Joosten V, Lokman C, van den Hondel CA, Punt PJ. Microb Cell Fact. 2003;2:1. PMID: 12605725
  4. Johnson M. Labome Validated Antibody Database. https://www.labome.com/method/Antibody-Structure-and-Fragments.html. Updated July 29, 2018. Accessed August 23, 2018.
  5. Prevodnik VK, Lavrenčak J, Horvat M, Novakovič BJ. Diagn Pathol. 2011;6:33. PMID: 21486448
  6. Frankel SR, Baeuerle PA. Curr Opin Chem Biol. 2013;17:385-392. PMID: 23623807
  7. Wang X, Mathieu M, Brezski RJ. Protein Cell. 2018;9:63-73. PMID: 28986820
  8. Dieckmann NMG, Frazer GL, Asano Y, Stinchcombe JC, Griffiths GM. J Cell Sci. 2016;129:2881-2886. PMID: 27505426 
  9. Thiery J, Keefe D, Boulant S, et al. Nat Immunol. 2011;12:770-777. PMID: 21685908
  10. US National Institutes of Health. ClinicalTrials.gov. https://clinicaltrials.gov. Accessed July 26, 2018.