The Chemistry Behind Antibody-Drug Conjugation
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1 Eran ella The Chemistry Behind Antibody- Conjugation Antibody- Conjugation (ADC) Dominant Investigator - Taking the advantage of the specificity of mab (monoclonal antybodies) to deliver potent cytotoxic drug selectively to antigen-expressing tumor cells. Chemistry allows to use highly potent drugs that could not be used alone. - o. of publication with the concept "antibody drug conjugated" over ther years: - Peter D. enter,.d. - B.A Biotechnology (Berkeley),.D. Chemistry (University of Illinois), Postdoctoral in the Max-Planck Institute for Experimental Medicine. Worked at Cytokine etworks, istol-myers-quibb esearch Institute. Current position: Vice president, eattle Genetic. (Development of potent drugs, novel linker systems and conjugation methodology) enior editor of Molecular Cancer Therapeutics Affilate Professor (University of Washington) Antibody- Conjugates - inical eports (clinicaltrials.gov 2012) Antibody- Conjugates - istory Agensys - 3 ADCs in ase I (auristatine) - carcinoma and prostate cancer Bayer ealthcare - 2 ADCs in ase I (Auristatine/maytansinoid) Paul Erlich "Magic Bullet" 2 2 C 2 C 2 MT-Ab oncovalent linked ADC tested in animal models umanized mabs reported First FDA approved ADC Mylotarg Mylotarg withdrown from market Kadcyla approved Biogen - 1 ADC in ase I (DM4) - breast cancer Biotest - 1 ADC in ase II (DM4) - myeloma BM - 1 ADC in ase I (duocarmycin) - non-odgkin's lymphoma Celldex - 1 ADC in ase II (auristatine) Immunogen - 2 ADCs in ase I (DM1 and DM4) Pfizer - 1 ADC in ase III - non-odgkin's lymphoma Progenics - 1 ADC in ase I (auristatine) - prostate cancer oche - 1 ADC in ase III and 2 ADCs in ase I (DM1) - breast cancer Discov. Today, Covalent linked ADC tested in animal models ADC with calicheamicin Adcetris approved anofi - 2 ADCs in ase II (DM4) - lymphoma and leukemia eattle Genetics - 1 ADC in ase III and 1 ADC in ase I (auristatine) - non-osdgkin's lymphoma and carcinoma 1
2 Eran ella The Chemistry Behind Antibody- Conjugation Mode of Action General Linkers - Use of highly potent drugs (Especially negative-charged drugs) - Ab can be also anti-cancer - is stable and usually inactive until it reaches the cancer cells ADC with a specific drug is usually more potent than the drug alone 2 2 amide C isothiocyanate thiourea haloacetyl thioether ImmunoGen Inc. Antibody- Conjugates - Components & Demands Attachment ite Linker maleimide -table -low hydrolysis thioether imple Conjugation Antibody: 1. Targets a well-characterized antigen with high tumor expression 2. Maintain all of it's properties upon conjugation to the drug 3. Minimal non specific binding Attechment site: 1. Typically through cysteine or lysine residues on the Ab 2. Variable drug:ab ratio or site-selective conjugation maleimidocaproyl Linker: 1. eavable or non cleavable 2. table with selective release of the drug : 1. ighly potent (usually 2-4 drugs per mab) 2. on-immunogenic 3. Could be linked to the Ab 4. Defined mechanism of action Current pinion in Chemical Biology, 2010, 14, 529 mercaptoacetamidocaproyl 2
3 Eran ella The Chemistry Behind Antibody- Conjugation Thiolation eagents 2 = mab or 2-iminothiolane "Traut's eagent" 1g = 3.5 $ C 1g = 7.4 $ C 2 K 2 C 3 quant. a 3 3 Ac 2 Canadian J. rg. Chem., 1984, 62(3), 586 Chem. Abstr., 1968, 68 C Ac Toluene reflux % /Me 67% 2 2 Et 3 TCEP MeC MM Me PABA PP Pyridine 2 p=7.4 2 Chem. Commun., 2013, 49, 8187 p=4.5 2 PABA 3
4 Eran ella The Chemistry Behind Antibody- Conjugation Bifunctional Linkers 2 Bioconjugate Chem., 2014, 25, 460 C 2 Piperidine/ Tol xone Misc. Linking with pecific elease Mechanism Piperidine J. Controlled elease, 2012, 161, 422 ydrazone (apid hydrolysis in the lysosome) B p=7.4 -Tol 2 - Disulfide (eduction in lysosome) 2 Mainly by Glutathione 2 Linking by ick bosutinib Val-Cit dipeptide (site-specific proteolysis) ometimes also e-lys copper-free click - developed by Bertozzi (2007) PA, 104(43), Can deconjugate (retro-michael) Can't deconjugate 3 JAC, 2013, 135,
5 Eran ella The Chemistry Behind Antibody- Conjugation Traceless Linkers 2 C thiazolidine (ydrolysis) Precise Controll on Conjugation to ynthesize homogeneous ADCs Advantages: 1. Known mab: ratio. 2. mab stability remains 2 xime Ligation C 2 2 Ellman eagent 2,2'-dithiopyridine (eduction) C 2 ature Protocols, 2013, 8, 2079 Genetically encoded unnatural amino acid with ortogonal chemical reactivity chultz, PA, 2012, 92(3), 13 2 PB, T, 30 min 1. TFAA 2. EDC, Bt 3 2 = auristatine 3. K 2 C 3 / Me 2 3 ick-like reaction for Tyrosine erceptin PP, Et 3 2. EtC 2 GD 2 DTT (dithiothreitol) (eland's eagent) C P C C TCEP Et B, Pyridine Barbas, JAC, 2010, 132, K 2 C 3 / Me
6 Eran ella The Chemistry Behind Antibody- Conjugation pacers elf-immolative pacers (Cont.) n n -C 2 elf-immolative pacers Examples -C Y Y Y -C 2 6
7 Eran ella The Chemistry Behind Antibody- Conjugation Adcetris (entuximab Vedotin) mab - entuximab, directs to protein CD30 (expressed in odgkin's lymphoma and large-cell lymphoma) Attachment ite - thiomaleimido caproyl Linker - Cathepsin (protease) cleavable linker (Val-Cit) pacer - PABA - Monomethyl auristatine E (MMAE) 2 MMAE - - antimitotic drug (inhibits mitosis, cell division), from the marine shell less Dolabella Auricularia - Blocking the polymerisation of tubulin times more potent than vinblastine Dolastatine 7
8 Eran ella The Chemistry Behind Antibody- Conjugation Adcetris (entuximab Vedotin) Pettit, JAC, 1989, 111(14), 5463 Dolastatine Cbz a, C 3 I TF 83% Cbz B 3, TF 95% Cbz 3 -Pyridine, DM 78% Cbz LDA, TF -78 o 87% total 33% separated Cbz (3,4, 5) C 3 2, BF 3 etherate 67% Cbz Me 2, Pd/C 63% Me Boc 1. B 3 - TF 2. modified wern 75% (2 steps) Boc LDA, Mg 2 47% after separation Boc Me 3 BF 4 DCM Boc Me K t Bu -20 o 57% Boc Me 1. 2 /Pd 2. TFA TFA 2 Me Boc Boc Mn 2 Boc 8
9 Eran ella The Chemistry Behind Antibody- Conjugation Adcetris (entuximab Vedotin) Tetrahedron, 2007, 63, 6115 Dolastatine Boc C ()-Boc-Isoleucine 1. CDI 2. Mg( 2 CC 2 CEt) 2 62% Boc Et u 2 [()-YP) 2, 12bar, 50 o, 24h 100% conversion 92:8 Boc Et 1. LMD. MPA, MeTf 2. aq. a / Et 60% (2 steps) Boc Me P 2 P 2 Boc Boc Et Boc Me ()-Boc-Proline Me Pyridine 77% Me Li 56% 1. Ipc 2 B 2. a % 99% ee P 3 P 3, DEAD 3 1. P 3, 4 2. DIBC 44% >99%ee Boc 9
10 Eran ella The Chemistry Behind Antibody- Conjugation Kadcyla (Trastuzumab emtansine) mab - Trastuzumab, targets E2 receptor, also stop cell groth alone Attachment ite - MCC (succinimidyl trans-4-(maleimidylmethyl)cyclohexane-1-carboxylate) - Mertansine (3.5 units/mab in avarage) Mertansine (DM1) - Thiol derivative of Maytansine - Antimitotic Me Me Me LiAl 4 TF 88% Me Me 1. MeC, K 2 C 3 2. a/me 90% Me Me 1. Ms, Et3 2. ai 94% Me Me CEt I 2, C 4 LDA 50% 1.DP, pts 2. Buli 3. Me Cu Me Li Cu TP Me I Me Me Li Cu 90% TP Me Me TP 1. pts/me 2. Mn 2 95% Me Me 2 LDA, TM 1. sec-buli Me Me 73% TM 2. Me Me Corey JAC, 1978, 100(9), 2916 Tel. Lett. 1978, 12, 1051 JAC, 1980, 102(4), Ac/aAc 10
11 Eran ella The Chemistry Behind Antibody- Conjugation Kadcyla (Trastuzumab emtansine) Ac Ac Ac 1. ame/me 2. gac 75% Acg Me 1. a 2. ab % Me 1. Trt, Pyridine 2. a (4 eq.) 3. isopropylbenzene sulfonyl imidazole 75% Trt Me Me MeLi, CuI Trt Me C 3 / 96% BF 3 Et 2 86% Et MEM 99% MEM MEM Me Me 1. nbuli 2. a, MeI Me Me Me MEM 1. C 3 Li Pb(Ac) 4 Me Me MEM Li TM then Pyridinium chloride 82% Me Me MEM 1. Me P Me Li 2. Bu 4 3. Mes % 2 4 Me Me Me 1. PP, Pyridine 2. 4 / t-butanol 3. g 2, CaC 3 76% Corey JAC, 1978, 100(9), 2916 Tel. Lett. 1978, 12, 1051 JAC, 1980, 102(4), 1439 Me Me (-)--Methylmeysenine 11
12 Eran ella The Chemistry Behind Antibody- Conjugation Mylotarg (Gentuzumab ozogamicin) mab - Gentuzumab (antibody to CD33 expressed in leukemia cells) Linker - includes ydrazone and stable - linkage - Calicheamicin Calicheamicin - from Micromonospora echinospora, Texas, Causes DA strand scission C 2 Me C 2 Me C 2 Me initiation Bergman Cycloaromatization DA ugar ugar ugar C 2 Me DA diradical 2 DA scission ugar 12
13 Eran ella The Chemistry Behind Antibody- Conjugation C 2 Me Et 3 i Bz Pd C-C acetyilide-aldehyde condensation tetronic acid ethylene glycol pts 60% DIBAL 84% MEM s-buli MEM Li Ipc 2 BMe MEM BIpc 2 (Z) 2 2, a MEM 1. TB, Im 2. C, Pyr TB Bz MEM 1. TBAF 2. wern 3. 2 Bz MEM a Bz MEM Bz MEM isoxazoline 51% after separation 1. ame 2. Cr 3, TM 4. Ac 2 5. Zn 2 Li TM Ac 1. wern 2. P 3 =CC 2 Me TM Ac C 2 Me icolaou, JAC, 1992, 114,
14 Eran ella The Chemistry Behind Antibody- Conjugation C 2 Me Et 3 i Pd C-C Bz TM Ac C 2 Me acetyilide-aldehyde condensation 1. K 2 C 3 /Me 2. TE triflate 3. TM Pd(P 3 ) 4, CuI 91% Et 3 i TM C 2 Me 1. Mo(C) 6 2. K 2 C 3 82% Et 3 i 2 C C 2 Me Pyridine Me 2 Et 3 i C 2 Me 1. i 2 2. Ac 2 Et 3 i C 2 Me th C KMD -90 o 48% Et 3 i C 2 Me th 1. Ms 2. i 2, Pyr Et 3 i th 1. Me 2 (99%) 2. Triphosgene, Pyr/Me (82%) 3. DIBAL, ab 4 (82%) 4. C, Pyr (84%) Et 3 i C 2 Me Bz icolaou, JAC, 1992, 114,
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