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Final Thoughts

Final Thoughts. -Overall, outcomes in ALL have come a long way since the sixties -Although we can achieve dramatic and sustained responses in childhood ALL, drug refractory relapse is a problem, especially in adults and high risk groups

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Final Thoughts

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  1. Final Thoughts -Overall, outcomes in ALL have come a long way since the sixties -Although we can achieve dramatic and sustained responses in childhood ALL, drug refractory relapse is a problem, especially in adults and high risk groups -We need drugs that can sustain remission or effectively treat relapse -Transplant is risky, particularly in adults

  2. Immunobiology of ALL -Monoclonal Abs have revolutionized the analysis and diagnosis of leukemias by recognizing specific cluster determinants on the cell surface -Investigators found that these same antibodies can selectively deliver therapy to leukemia cells in vivo -The accessibility of hematopoietic malignancy is favorable for this approach

  3. MAbs Commonly Used in Leukemia Immunophenotyping T-Cell • CD1, CD2, CD3, CD4, CD5, CD7, CD8, CD10 B-Cell • CD10, CD19, CD20, CD22, CD79a Myeloid • CD11, CD13, CD14, CD15, CD33 Non-lineage • CD34, CD38, HLA-DR, CD45 These MAb are used to identify ALLs of T-cell, B-cell, and mixed lineages.

  4. Why direct a molecule with anti-CD22 and anti-CD19 -Studies in mice showed that the combination was better than the individual antibodies -A mixture of anti-CD22 and anti-CD19 ricin immunotoxins were developed and showed promise in phase 1 studies -A genetically engineered monospecific anti-CD22 immunotoxin recently tested in a phase 2 study for Hairy Cell Leukemia >60% complete response rate. -Our own data has been quite convincing.

  5. s s s s Hinge s s s s s s s s s s s s VH VH s VH s s s VL VL s s s s VL s s CH1 CH1 s s CL CL s s sFv s s s s CH2 CH2 Conventional Antibody CH3 CH3 VL VH DT2219 BLT s s s s s VH VL s s s Anti-CD22sFv Anti-CD19sFv Toxin

  6. The Process -Splice genes together and then express in inducible competent bacteria -Lyse bacteria, extract and purify protein -Test protein against CD22+CD19+ Daudi or Raji B Lymphoma Cells. -Vial drug cGMP -File pre-IND 95 kDa 1 2 3 4 5 6 7 8

  7. Bispecific Ligand Directed Toxins (BLT) as a Solution -Powerful, catalytic inhibitors of protein synthesis -Mechanism of action very different from chemo. Thus, can be given when chemo can no longer be given -Criteria for a successful BLT: *Bispecific has greater activity than its monospecific counterparts *Bispecific is superior to a mixture of the monospecific counterparts indicating an advantage of both ligands on the same molecule -Genetically modifiable Genetic engineering used to increase affinity and product yield and diminish immunogenicity

  8. BioAssay - Proliferation % Control Response

  9. Therapy of Scid Mice With Systemic Cancer Given DT2219 Measure SURVIVAL Day 3 Day 0 Inject IV 106 Cells Start Treatment In press: Leukemia Research

  10. Sensitive Detection of B Cell Malignancy in Scid Mice in Real Time Raji Cancer Cells -Transfect Luciferase and GFP genes DUAL REPORTERs! Clone via FACS To obtain stable transfectant -The bioluminescent reaction releases light and the light signal can be used for analyte quantification • Use a very sensitive photon detector which can detect the emission of even a • few photons • -GFP is fluorescent! Must use a different detector. Different information

  11. Conclusions - BLTs are highly effective in inhibiting malignant B cells. -Our BLT is selective, potent, and capable of curing mice with systemic human B cell cancer. -The combination of both sFvs on the same single chain molecule are necessary for the high degree of effectiveness of DT2219. -A clinical batch has been prepared and FDA IND approved for testing at Scott and White -Since this DT is an established inhibitor of protein synthesis, DT2219 may be valuable as alternative drug therapy to sustain remission or treat relapse -If immunogenicity is a problem in our trial, we have found a solution.

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