What is Bruton's tyrosine kinase
understand it, Bruton's tyrosine kinase (Btk) is a
pathway that controls the function of the B cell antigen
receptor (BCR), the "business end" of the
The BCR is the
receptor that binds to pathogens (bacteria, virus ...) that
body. In a sense, the BCR is the b-cell's reason for being ... what
it does for a living.
illustration, the Ag represents an antigen bound to the
B-Cell Receptor, and the Bruton's tyrosine kinase
(Btk) is downstream of this molecule.
When the b-cell antigen receptor binds to an antigen a cascade
of signals take place within the cell, which promotes the
prolonged survival of the cell and cell cycle progression.
(Just what we don't want to happen when the b-cell is abnormal -
a lymphoma cell.)
Drugs that bind to BTK may preferentially target mature b-cells
(not skin cells, etc) preventing the BCR from working, and in
turn limiting the survival of these cells.
Thus, btk-inhibitors may prove to be another important way to
manage b-cell lymphoma, or improve the cure rate, with less
toxicity than less-specific chemotherapy drugs. The BTK
inhibitors may be used as a single agent or with standard
therapies -- similar to how Rituxan is used today.
Abstract Title: Regulation of B lymphocyte development and
activation by Bruton's tyrosine kinase
Agents targeting btk in clinical phase testing
In the News
Acalabrutinib received an FDA breakthrough designation for
the treatment of Mantle Cell Lymphoma.
This designation is given
when "preliminary clinical evidence indicates that the drug
may demonstrate substantial improvement over existing
therapies on one or more clinically significant endpoints,
such as substantial treatment effects observed early in
Hereís the (no-longer
recruiting) study thatís the likely basis for the
Acalabrutinib (ACP-196): a selective second-generation BTK
inhibitor | Journal of Hematology & Oncology | Full Text
"Acalabrutinib (ACP-196) is a novel irreversible
second-generation BTK inhibitor that was shown to be more
potent and selective than ibrutinib. This review summarized
the preclinical research and clinical data of acalabrutinib."
Comment: Acalabrutinib is in the same class as Ibrutinib
(similar target, also an oral drug). Ibrutinib is already
approved for use in MCL. So we might safely assume that the
efficacy and/or safety appears to be substantially better
for Acalabrutinib. However, I could not find an published
reports on outcomes in the trial above - nor a statement by
FDA on the basis for the decision. In any case, it's very
big and good news.
Fact Sheet: FDA Breakthrough Therapies
2015: Experts discuss Initiation and Discontinuation of
* Ibrutinib is an
irreversible molecular inhibitor of ITK driving a
Th1-selective pressure in T lymphocytes
This technical paper
describes an off-target effect of ibrutinib that could,
possibly, limit its long term use (as noted by Dr. Bryd in
the discussion that follows). The off-target effect on
t-cells might also further explain its efficacy as touched
on in this snip:
This report establishes a previously unidentified
immunomodulatory mechanism of action for ibrutinib that has
the potential to expand its antitumor applications. Aside
from T-cell malignancies for which ITK acts as a driver, it
is well appreciated that tumors develop a prosurvival niche
enhanced by Th2-polarized CD4 T cells.1,2 In leukemia, these
cells provide constitutive IL-4, IL-6, and CD40L
stimulation, driving the expansion of disease.44
* ASH 2012 Paper:
The Brutonís Tyrosine Kinase Inhibitor Ibrutinib (PCI-32765) Is
Active and Tolerated in Relapsed Follicular Lymphoma
* Approval for CLL - Medscape 2014:
FDA Sends Valentine to CLL Patients (Cheson video)
* Patient Power 2013:
Video of Dr Sharman
discussing Ibrutinib and other options
Promising Advances in Treating Mantle Cell Lymphoma
* Dr Sharman 2013:
Ibrutinib gets first approval in Mantle Cell Lymphoma
FDA Approves Ibrutinib for Mantle Cell Lymphoma
*The Street 2013
Pharmacyclics' Lymphoma Drug Receives FDA Approval. Cost:
$130,000 Per Year!
* Picture it: B-cell receptor
and related pathways:
Find Clinical reports:
Lymphomas that arise from mature
from stem cells in the bone marrow. These specialized
immune cells express different features as they mature (on there
cell surface, but also internally).
This provides opportunities to target lymphomas that arise from
defective mature b-cells (such as follicular and DLBCL).
Therapy that binds such targets will not affect stem cells or
immature b-cells - allowing for the restoration of this part of
the immune system when the therapy is discontinued.
Rituxan is an example of a therapy that is specific to mature
b-cells, as it targets cd20, which is not expressed on immature
b-cells as shown in the image that follows:
b-cell maturation on nature.com.
In the illustration, the arrows show where CD20 and other
surface markers on mature b-cells are first expressed.
Clinical trials for PCI-32765
(Ibrutinib) targeting Bruton's tyrosine (Btk):
Related Articles and information: