Targeting the the B Cell Receptor - BCR

[Guest guest]

It's early in the development of this targeted agent, but perhaps not too

early to consider as therapy given its good (so far) safety profile and the

compelling rationale for the target, BTK.

* Rationale for target: " Bruton's tyrosine kinase (BTK) is the gene that is

disrupted in the human disease X-linked agammaglobulenemia (XLA). Patients

with XLA are devoid of mature B-lymphocytes and immunoglobulins in the

bloodstream, but are otherwise healthy. XLA thus provides strong clinical

rationale for development of a novel therapeutic drug targeting Btk for safe

inhibition of B-cell mediated diseases. "

* Early report on safety:

http://ash.confex.com/ash/2009/webprogram/Paper22659.html

Snip: " The study is currently open and enrolling. Seven patients (1 DLBCL,

2 MCL, 4 FL) with a median of 3 prior therapies have been enrolled in the

first cohort (one more patient than originally planned). Therapy has been

extremely well tolerated with no DLT or greater than grade 2 hematological

or non- hematologic toxicity. Six patients have completed at least 1 cycle.

* Clinical trials recruiting, or soon to be: http://bit.ly/bpHoAm

Eligibility: *Recurrent surface immunoglobulin positive B cell non-Hodgkin's

lymphoma (according to WHO classification) including small lymphocytic

lymphoma/chronic lymphocytic leukemia (SLL/CLL). *Bi-dimensional measurable

disease (¡Ý 2 cm diameter or for CLL ¡Ý 4000 leukemia cells/mm3).

*Have failed ¡Ý 1 previous treatment for lymphoma and no standard therapy is

available. Patients with diffuse large B cell lymphoma must have failed,

refused or be ineligible for autologous stem cell transplant.

TECHNICAL background on BTK drug target from sponsor's poster:

http://www.pharmacyclics.com/img/ASH2007_Btk_PCI-32765_poster_final.pdf

Several lines of evidence suggest that BCR signaling is tonically

activated in lymphoma and that a functional BCR is required for

lymphoma cell survival 3.

¨C sIg expression is maintained in lymphoma.

¨C Ig translocations (e.g. Bcl-2) usually occur in non-productive Ig loci.

¨C Resistance to anti-idiotype therapies is associated with mutation rather

than inactivation of Ig expression.

¨C A functional BCR is required for mature B cell survival in mouse4.

¨C RNAi of Ig¦Á inhibits growth of lymphoma cell lines5.

¨C Primary follicular lymphoma cells show enhanced BCR signaling compared to

infiltrating normal B cells6 and Syk and BLNK are tonically phosphorylated

in primary DLBCL7.

References from same

1. Pan, Z. et al. ¡°Discovery of Selective Irreversible Inhibitors for

Bruton's

Tyrosine Kinase.¡± ChemMedChem. 2007 Jan 15;2(1):58-61

2. Li, SJ, Pan, Z., et al ¡°A Selective Kinase Probe for Btk¡±, in prep.

3. Kuppers, R. ¡°Mechanisms of B cell lymphoma pathogenesis.¡± Nat Rev

Cancer

5:251 (2005).

4. Kraus M, et al. ¡°Survival of resting mature B lymphocytes depends on BCR

signaling via the Ig¦Á/¦Â heterodimer.¡± Cell 11:787 (2004).

5. Gururajan, M. et al ¡°Constitutive B cell receptor signaling is critical

for basal

growth of B lymphoma¡±, J Imm (2006).

6. Irish JM, et al. ¡°Altered B-cell receptor signaling kinetics distinguish

human

follicular lymphoma B cells from tumor-infiltrating nonmalignant B cells.¡±

Blood 108:3135 (2006).

7. Chen L, et al.¡±Syk-dependent tonic B-cell receptor signaling is a

rational

treatment target in diffuse large B-cell lymphoma.¡± Blood (epub 11/15/07).

All the best,

~ Karl

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