15. CD33 mAB
The Good
• Endocytic receptor
• Rapidly Recycled
• Level of expression not
correlated to response
• IgG4 longest serum half life
• Least ADCC
• No Complement Fixation
The Bad
• Present in liver cells
• Naked antibody ineffective
16. Linker
The Good
• pH Soluble degrades within
lysozymes
• Average 2.5 molecules
calechiamicin per ab
The Bad
• Distributed to lysine
residues – less predictable
stoichiometry and
homogeniety
• 50% Unconjugated
• Heavily conjugated removed
from circulation
17. Calicheamicin
The Good
• Binds to minor grove of
DNA causes double strand
DNA breaks
The Bad
• Complex molecule difficult
to manipulate
• PgP substrate
• Hydrophobic limits
solubility
22. Myelotarg: Lessons Learned
• Calicheamicin
– Potent but PgP target
– Hepatotoxic
– Suboptimal for conjugation
– Diminishes serum half life
• Linker
– Unable to achieve homogenous drug
– pH based results in free drug
• Antibody
– Good target for disease but hepatic expression
mediates toxicity
27. Rituxan Refractory Indolent NHL
• 43 pt no response or PD
within 6 months to R, R-
Chemo, RIT
• 65% Low PLT, 53% Neut
• 48% LFT
• 53% ORR
• 19% CR
28. Relapsed DLBCL
• All 63 patients early
relapse, prior rituxan,
high IPI
• ORR 35%
• 70% Thrombocytopenia
• 40% LFT’s
• 2 cases of VOD
29.
30. Inotuzumab Summary
First in Class Molecule
• Not without symptoms
• Moderate heme tox
• Worrisome liver picture
• Has efficacy in difficult
populations
Transplant Ineligible DLBCL
• R-Ino VS. R-Benda or R-Gem
32. T-DM-1
The Good
• Thio-ether linker
• Zwitterion
• 50-4000x microtubule drugs
The bad
• Lysine linked stoichiometry
• Hydrophobic T1/2 4d
instead of 3 wks for naked
41. • Combinatorial Synthesis
• Water Soluble
• Built in Linker
• High Potency
• Val-Cit plasma stable
but rapid cathepsin-B
• Spacer for proteolysis
• T1/2 1wk
Right Drug & Right Linker
EFS with relapse within one year or greater than one year
3 year efs prior rtx 21% vs 47%, early relapse 20 vs 45%, secondary aaIPI 2-3 18% vs 40 (0-1)
German Dye Industry – histochemistry, late 1800’s, early 1900’s. Nobel Prize 1908, became interested in various toxins, eg Ricin, Diphtheria – 20 years before penicillin, 40 years before goodman’s first mustard experiments, 90 years before rituxan
Two ways to work – extracellular drug release or internalization
Small lab efforts (not pharma supported), poor antibody selection, drugs were known entities with established therapeutic index. tried to overcome this my polyconjugation but this resulted in decreased half lives, not necessarily internalizing antibodies
Monoclonal technology became available in 1975. Vinca alkaloids conjugated to mouse antibodies fail too (Eli Lilly), doxorubicin – BMS – conjugate immunogenicity, low drug potency (delivered to tumor but weak drugs), unstable linker, antigen exposure on normal tissue
Humanized antibody, linker
Acid labile covalent linker which allows stability in physiologic buffers (pH 7.4) but efficient release inside lysosomes ph=4, 2-3 molecules per antibody
Nearly 60% response but 2/49 died yellow, ¼ pts undergoing x-plant had VOD
Lysine leads to random distribution and is TDM-1 and myelotarg. Cystiene can lead to 8 which is bulky and rapidly cleared but recombinant technology and selective reduction allows 4 drugs per molecule at defined places and scaled manufacturing with small percentage of 0/8 drugs per ab
