Question

Q3. During the lectures of Part-14, you learned that anti-CD20 antibodies coupled with a potent-toxin may be used to kill tumor B cells.

Suppose that CD20 is expressed on by hematopoietic stem cells and all the developmental stages of B cells.

Do you think that in this case, anti-CD20 antibodies coupled with a potent-toxin can still be used to kill B cell tumor cells?

Yes, No….please explain why.

Answer 1

CD-20 is surface B-cell marker .....CD20 is a general B cell marker that is expressed during B cell differentiation from the pro-B cell phase until the plasma cell stadium.

Yes anti-CD20  antibodies coupled with a potent-toxin can still be used to kill B cell tumor cells.. because Therapeutic monoclonal antibodies (mAbs) that target the CD20 antigen on B cells are successfully used in the clinic for the depletion of B cells to treat various forms of cancer and autoimmune diseases....CD20 mAbs can induce tumor killing via various mechanisms, such as direct induction of apoptosis, antibody-dependent cell-mediated cytotoxicity (ADCC) or complement-dependent lysis (CDC)....

The chimeric mAb rituximab (RTX, Roche / Genentech) was the first FDA-approved CD20 mAb. It is approved to treat CD20 positive B cell malignancies; e.g. non-Hodgkin lymphoma and chronic lymphocytic leukemia (CLL)... It is most commonly given with cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP), but also with other chemotherapeutic combinations, with small molecule targeted therapies, as a monotherapy, or as maintenance therapy...

CD20 is a tetra-transmembrane protein with an intracellular N- and C-terminal region and two extracellular loops, generally referred to as the small and large loop, and are the portion of the peptide which is targeted by current therapeutic mAbs and CD20 is expressed as part of B-cell development,. It is known to be involved in store-operated calcium influx, and loss of a cytoplasmic portion of CD20 inhibits activated BCR mediated intake of calcium......

Anti-CD20 mAbs also have the capacity to redistribute CD20 within the plasma membrane into lipid rafts . Functionally, this redistribution may be important for the role of CD20 in BCR signaling . However, it also has significant implications for anti-CD20 antibodies themselves. The ability (or lack thereof) of mAbs to redistribute CD20 into lipid rafts has served as a useful classification system for anti-CD20 antibodies . mAbs such as rituximab and ofatumumab that bind CD20 and cause compartmentalization into lipid rafts are classified as type I antibodies, whereas those that bind CD20 but cause no redistribution, such as obinutuzumab, are known as type II antibodies..

The redistribution of CD20 and the associated mAb into lipid rafts is also functionally important with regard to the antibody effector functions induced. Due to the enhanced clustering of antibody Fc regions, type I antibodies are able to potently induce complement-dependent cytotoxicity (CDC). type II antibodies have been reported to induce a greater degree of directly induced, non-apoptotic cell death upon binding to target cells ). This mechanism has been shown in both B-cell lines as well as primary B-CLL cells . The enhanced clustering of type I antibodies renders them more susceptible to internalization, resulting in lysosomal degradation and a reduction in surface CD20 expression ).