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Immunoconjugates 2 Search Strategies at the Interface of Chemistry and Biology: Immunoconjugates 2 Agenda • Overview • Immunoglobulin (antibody) nomenclature in CAS REGISTRYSM • Search examples • Classification codes 3 Immunoconjugates are antibodies conjugated to a toxin, radioisotope, or label • A cytotoxic drug is linked to a monoclonal antibody for delivery to a target cancer cell that recognizes the antibody mAb - linker - cytotoxin • Ideally, conjugates are stable until delivered to cancer cells and don’t release their “payloads” to healthy cells ‒ Advances in stable linkers have greatly increased efficiency of immunoconjugates • Antibodies to unique or overexpressed antigens for cancer reduces take-up by healthy cells 4 How immunoconjugates work 1. Antibody binds to cognate antigen on target tumor cell 2. Immunoconjugate complex is internalized via endosomal/lysosomal pathway 3. Depending on linker, the cytotoxic agent is released via chemical cleavage or lysosomal degradation, delivering the drug directly to the tumor cell 4. Cytotoxins are mainly two categories: DNA modifying agents, or microtubule disrupting agents 5 Example of an immunoconjugate complex Brentuximab vedotin - Adcetris® Image source: https://en.wikipedia.org/wiki/File:MMAE-MAB-conjugate_skeletal.svg. T his image is in the public domain. 6 Searching for immunoconjugates will have to account for what is available in a database • What information is indexed? ‒ Structure ‒ Sequence ‒ Controlled terms • Pieces and parts? • Entire complex? 7 CAS REGISTRY record for brentuximab vedotin RN 914088-09-8 REGISTRY ED Entered STN: 28 Nov 2006 CN Immunoglobulin G1, anti-(human CD30 (antigen)) (human-mouse monoclonal cAC10 γ1-chain), disulfide with human-mouse monoclonal cAC10 κ-chain, dimer, complex with N-[[[4-[[N-[6-(2,5-dihydro-2,5-dioxo-1H-pyrrol-1-yl)-1- oxohexyl]-L-valyl-N5-(aminocarbonyl)-L-ornithyl]amino]phenyl]methoxy] carbonyl]-N-methyl-L-valyl-N-[(1S,2R)-4-[(2S)-2-[(1R,2R)-3-[[(1R,2S)-2- hydroxy-1-methyl-2-phenylethyl]amino]-1-methoxy-2-methyl-3-oxopropyl]-1- pyrrolidinyl]-2-methoxy-1-[(1S)-1-methylpropyl]-4-oxobutyl]-N-methyl-L- valinamide (CA INDEX NAME) OTHER NAMES: CN Adcetris CN Brentuximab vedotin Immunoconjugates in REGISTRY receive a CN CAC10-vcMMAE CN cAC10-vcMMAE descriptive CA Index Name that includes the CN SGN 35 antibody (immunoglobulin) name and the MF Unspecified chemical attachment. CI MAN SR CA LC STN Files: ADISINSIGHT, CA, CAPLUS, CBNB, CHEMCATS, CHEMLIST, EMBASE, IMSPATENTS, IMSRESEARCH, IPA, TOXCENTER, USPAT2, USPATFULL *** STRUCTURE DIAGRAM IS NOT AVAILABLE *** 126 REFERENCES IN FILE CA (1907 TO DATE) 6 REFERENCES TO NON-SPECIFIC DERIVATIVES IN FILE CA 132 REFERENCES IN FILE CAPLUS (1907 TO DATE) Manual Registrations in CAS REGISTRY • MAN - Class identifier assigned to a substance which cannot be assigned a structure connection table by the CAS Registry System ‒ Substances with a complete structure, but which cannot be processed by the CAS Registry System, e.g., > 253 non-hydrogen atoms ‒ Substances with an unknown or generic structure ‒ Multicomponent substances consisting of components with complete structures and components with unknown or generic structures 9 Examples of immunoconjugates in DCR AN.S DCR-728845 CN.P BRENTUXIMAB-VEDOTIN SY ADCETRIS; BRENTUXIMAB VEDOTIN; BRENTUXIMAB-VEDOTIN; CAC10-MMAE4; CAC10-MMAE8; CAC10-VAL-CIT-MONOMETHYL AURISTATIN E; CAC10-VAL-CIT-VEDOTIN; CDX-011; CR-011-VC-MMAE; CR-011-VC-VEDOTIN; GLEMBATUMUMAB VEDOTIN; GLEMBATUMUMAB-VC-MMAE; GLEMBATUMUMAB-VC-VEDOTIN; SGN-35 NO STRUCTURE DIAGRAM AVAILABLE FOR THIS ACCESSION NUMBER CMT The peptide monomethyl auristain E conjugated to the chimeric anti-CD30 antibody, cAC10. MF Unknown AN.S DCR-271958 CN.P CANTUZUMAB MERTANSINE SY CANTUZUMAB MERTANSINE; CANTUZUMAB-MERTANSINE; SB-408075 CMT An antibody-directed small-molecule cytotoxic agent. It is a conjugate of the humanized monoclonal antibody C242 with a semisynthetic maytansinoid DM1 MF Unknown 10 Search strategies for immunoconjugates will be dependent on the area of interest Immunoconjugate piece Search strategies may include Antibody or antibody fragment Sequence Nomenclature Keywords and antigen terms Linker Structure Cleavable vs. non-cleavable Keywords Natural vs. non-natural Spacers, stretchers, connectors, attachments Cytotoxin Structure Nomenclature Class of substances Whole immunoconjugate Nomenclature Class of substances via keywords A comprehensive search might encompass all of these approaches. 11 Antibodies (immunoglobulins) have a Y-shaped structure Antigen binding site Antigen binding site CAS indexes CDR = complementarity determining immunoglobulins in region REGISTRY by name and VL = variable region - light chain by sequence, if known. VH = variable region - heavy chain SM In CAplus they are CL = constant region - light chain indexed as Controlled CH = constant region - heavy chain Terms. 12 What gets a CAS Registry Number® (RN)? • CAS registers the immunoglobulin, with a descriptive CA Index Name and sequence, if disclosed • CAS registers discrete chemical substances that can be part of the synthesis of a mAB conjugate, e.g., the starting materials and final products up to the point of attachment to the mAb if the reference discloses the synthesis • The final immunoconjugate will receive a RN, with a CA Index Name and usually the USAN name • CAplus indexing may include the final RN, or it may be indexed as a derivative of the drug or a derivative of the immunoglobulin 13 Vedotin is the cytotoxin, linker and attachment RN 646502-53-6 REGISTRY ED Entered STN: 05 Feb 2004 CN L-Valinamide, N-[[[4-[[N-[6-(2,5-dihydro-2,5-dioxo-1H-pyrrol-1-yl)-1- oxohexyl]-L-valyl-N5-(aminocarbonyl)-L- ornithyl]amino]phenyl]methoxy]carbonyl]-N-methyl-L-valyl-N-[(1S,2R)-4- [(2S)-2-[(1R,2R)-3-[[(1R,2S)-2-hydroxy-1-methyl-2-phenylethyl]amino]-1- methoxy-2-methyl-3-oxopropyl]-1-pyrrolidinyl]-2-methoxy-1-[(1S)-1- methylpropyl]-4-oxobutyl]-N-methyl- (CA INDEX NAME) OTHER NAMES: CN 36: PN: WO2007140371 PAGE: 273 claimed protein CN Maleimidocaproyl-valine-citrulline-p-aminobenzoyloxycarbonyl-monomethyl auristatin E CN mc-vc-PAB-MMAE CN VcMMAE CN Vedotin FS PROTEIN SEQUENCE; STEREOSEARCH MF C68 H105 N11 O15 SR CA LC STN Files: CA, CAPLUS, CASREACT, CHEMCATS, EMBASE, TOXCENTER, USPAT2, USPATFULL **RELATED SEQUENCES AVAILABLE WITH SEQLINK** 14 Immunoglobulin nomenclature used by USAN and World Health Organization (WHO) • Names follow the general format: ‒ Prefix - target - species of origin - mab TARGET SPECIES OF ORIGIN Example -t(u)- tumor -o- mouse Ibritumomab -l(i)- Immuno- -zu- humanized Daclizumab modulating -c(i)- cardiovascular -xi- chimeric Abciximab -t(u) tumor -u- human Olaratumab 15 CAS immunoglobulin nomenclature is descriptive Format Immunoglobulin _____, anti-(_____) fragment (animal source monoclonal heavy chain), disulfide with animal source monoclonal light chain, dimer Example CN Immunoglobulin G1, anti-(human interleukin 2 receptor) (human- γ mouse monoclonal clone 1H4 1-chain), disulfide with human-mouse monoclonal clone 1H4 light chain, dimer (CA INDEX NAME) CN Daclizumab CAS Index Name identifies the immunoglobulin class (Immunoglobulin G1) and the cognate antigen (human interleukin 2 receptor). Human-mouse indicates a humanized antibody. 16 Immunoconjugate nomenclature combines the descriptive immunoglobulin name with the chemical name of the organic attachment CN Immunoglobulin G1, anti-(human p185neu receptor) (human-mouse monoclonal rhuMab HER2 γ1-chain), disulfide with human-mouse monoclonal rhuMab HER2 light chain, dimer, tetraamide with N2′-[3- [[1-[(4-carboxycyclohexyl)methyl]-2,5-dioxo-3-pyrrolidinyl]thio]- 1-oxopropyl]-N2′-deacetylmaytansine OTHER NAMES: CN Kadcyla Green text is the immunoglobulin nomenclature, CN PRO 132365 purple text is the organic linker and cytotoxin. CN T-DM 1 CN Trastuzumab emtansine CN Trastuzumab-MCC-DM 1 MF Unspecified CI COM, MAN SR CAS Client Services LC STN Files: ADISINSIGHT, CA, CAPLUS, CBNB, CHEMCATS, CHEMLIST, EMBASE, IMSPATENTS, IMSRESEARCH, IPA, TOXCENTER, USPATFULL *** STRUCTURE DIAGRAM IS NOT AVAILABLE *** 17 Use immunoglobulin nomenclature to collect a set of antibodies in REGISTRY => FILE REGISTRY => S (IMMUNOGLOBULIN (L) ANTI (L) CD44)/CNS L1 307 (IMMUNOGLOBULIN (L) ANTI (L) CD44)/CNS Nomenclature searches in the Chemical Name Segment field (CNS) or Basic Index are a quick way to find sets of named antibodies in REGISTRY. Use sequence searches for more comprehensive searching. => S (IMMUNOGLOBULIN (L) HUMAN (L) .KAPPA. (L) DNA (L) SYNTHETIC) L2 1209 (IMMUNOGLOBULIN (L) HUMAN (L) .KAPPA. (L) DNA (L) SYNTHETIC) => S L2 AND P/DT AND CLAIMED L3 1191 L2 AND P/DT AND CLAIMED 18 Search for the cytotoxin Search Question Find relevant patent references for immunoconjugates that have maytansinoid cytotoxins. Maytansine 19 Search Strategy 1. Search the cytotoxin substructure in REGISTRY 2. Crossover to HCAplus and refine 3. Search cytotoxin substructure in MARPAT® and WPINDEX, find bibliographic references 4. Use DUP IDE and FSORT to group by patent family 5. Use the Patent Family Manager to extract one record from each family 6. Display answers 20 Run the substructure search in REGISTRY => FILE REGISTRY => Uploading . L1 STRUCTURE UPLOADED => D L1 HAS NO ANSWERS L1 STR The epoxide ring was left => S L1 SSS SAM off in the substructure FULL FILE PROJECTIONS: ONLINE **COMPLETE** search, since de-epoxy L2 50 SEA SSS SAM L1 derivatives do not include the ring. => S L1 SSS FULL L3 1007 SEA SSS FUL L1 => SAVE TEMP MAYTANSIN/A ANSWER SET L3 HAS BEEN SAVED AS 'MAYTANSIN/A' 21
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