Calicheamicin derivatives and antibody drug conjugates thereof
Inventors
Ahmad, Omar Khaled • Brown, Stephen Paul • DIRICO, Kenneth John • Dushin, Russell • Filzen, Gary Frederick • PUTHENVEETIL, SUJIET • Strop, Pavel • Subramanyam, Chakrapani • Tumey, Lawrence N.
Assignees
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Publication Number
US-11993625-B2
Publication Date
2024-05-28
Expiration Date
Abstract
The present invention is directed to novel calicheamicin derivatives useful as payloads in antibody-drug-conjugates (ADC's), and to payload-linker compounds and ADC compounds comprising the same; to pharmaceutical compositions comprising the same and to methods for using the same to treat pathological conditions such as cancer.
Core Innovation
The invention relates to a compound of Formula (IIA), or pharmaceutically acceptable salts thereof, with substituent variation defined by selections for R3, X, and R10. R3 is selected from —CH3, —CH2CH3, and —CH(CH3)2, and X is selected from substituted alkyl, carbocyclyl, heterocyclyl, phenyl, and heteroaryl options, with X optionally further substituted by 1 to 8 G.
R10 is defined as —R10a-R10b, where R10a is either absent or —(CH2)n— optionally substituted by G, and R10b is selected from hydroxyl, cyano, phosphonic acid, carboxylic acid, ester, amide, amine, and related carbonyl-containing groups, with additional amino-acid-based variation through R11. The linkage group L is defined as -LB-LA-, with LA selected from —NHR and LB defined by LB1, LB2, and LB3, where LB1 is absent, LB2 is either absent or selected from LB3, and LB3 is AA0-12 with AA independently a natural amino acid or a non-natural amino acid.
The disclosure further defines extensive substituent sets for G, E, and R, including aryl and heteroaryl substitution limits and ring-forming options for two or more R groups. The partial content also describes calicheamicin-derived linker-payload and ADC constructs, including antibody conjugates linked through linker radicals, anti-CD33 ADC examples, engineered cysteine antibody conjugation, and characterization by HPLC, LC-MS, SEC, HIC, and deconvolution analysis.
Claims Coverage
The provided claim set centers on one independent claim defining a compound of Formula (IIA) or a pharmaceutically acceptable salt thereof, with coordinated structural variability across R3, X, R10, R11, and the linker group L. Dependent claims mainly refine the L subgroups and add a pharmaceutical composition wrapper, while the partial content also refers to antibody conjugate embodiments.
Formula (IIA) compound scaffold with R3 and X variability
A compound of Formula (IIA), or a pharmaceutically acceptable salt thereof, wherein R3 is selected from —CH3, —CH2CH3, and —CH(CH3)2, and X is selected from substituted alkyl, carbocyclyl, heterocyclyl, phenyl, and heteroaryl options, with X optionally further substituted by 1 to 8 G.
R10 definition including R10a and R10b
R10 is —R10a-R10b, wherein R10a is either absent or —(CH2)n— optionally substituted by 1 to 8 G, and R10b is selected from —OH, —CN, —PO3H, —CO2H, —CO2C1-C4 alkyl, —CO—R11, —NH—R11, —N(C1-C4 alkyl)-R11, and related amide and carbonyl-containing variants, with R11 including natural or non-natural amino acid-based options.
Linkage group L as -LB-LA- with amino-acid-based LB3
L is -LB-LA-, wherein LA is selected from —NHR, and LB is LB1-LB2-LB3 with LB1 absent, LB2 either absent or selected from LB3, and LB3 as AA0-12, where AA is independently a natural amino acid or a non-natural amino acid.
Variable substituent set R with ring-forming capability
Each R is independently selected from H, alkyl, alkenyl, alkynyl, halo, hydroxyl, alkoxy, amino and substituted amino, nitro, aryl, and heteroaryl groups, with two or more R optionally joining to form a ring or rings and with optional substitution on aryl and heteroaryl groups within specified limits.
Pharmaceutical composition
A pharmaceutical composition comprising an effective amount of the compound of claim 1, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable diluent, carrier, or excipient.
The claim coverage is anchored by a Formula (IIA) compound with defined R3 and X substitution, an R10 group built from R10a and R10b with amino-acid-based R11 variation, and a linker group L defined as -LB-LA- with AA0-12-based LB3. The dependent and related claim language further supports broader substituent sets, ring formation by R groups, and a pharmaceutical composition context.
Stated Advantages
Improved potency and therapeutic window by limiting premature disulfide activation toxicity.
Documented Applications
Antibody-drug conjugate (ADC) use through connecting calicheamicin payloads to antibodies using the described linker unit L.
Cancer treatment context, including anti-CD33 ADC examples and cancer-treatment methods.
Engineered cysteine antibody conjugation to calicheamicin linker-payload ADC components for analytical and biological evaluation.
In vivo and cell-based evaluation, including AML xenograft tumor-growth studies, cytotoxicity testing, and comparison to Mylotarg and negative control ADCs.
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