Antibody-drug conjugates and uses thereof
Inventors
LI, Lele • Huang, Changjiang • SUN, Youxiang • Liu, Lina
Assignees
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Publication Number
US-11596693-B2
Publication Date
2023-03-07
Expiration Date
Abstract
Provided is an antibody-drug conjugate (ADC) using one or more cysteine or derivatives thereof as linkers to couple one or more drugs at the limited binding sites of an antibody, making it possible to produce an ADC product with high drug payload, or to choose a drug with less toxicity, thereby obtaining an ADC product with wide therapeutic window. In addition, since a plurality of drugs may be coupled to one binding site, the ADC products obtained by the method of the present disclosure have better uniformity in the case of same DAR value. Moreover, the amount of antibody required for production may be greatly reduced, thereby lowering the cost. Compared with the antibody-drug conjugates coupled only one drug, the antibody-drug conjugates produced by the method of the present disclosure have the same inhibition or killing effect on tumor cells while using fewer drugs for coupling to the same site.
Core Innovation
The invention relates to antibody-drug conjugates in which an antibody or a functional binding fragment thereof is joined through a branching conjugation structure to one or more active drugs. The disclosure presents general structures expressed by formula (I) to formula (IV), where A is an antibody or a functional binding fragment and B1 to Bn are branch units linked to active drugs, and states shortcomings of amide coupling, thiol coupling, and cross-linking or bridge coupling in relation to heterogeneity and stability.
The ADC includes linker moieties L1 to Ln+1 with covalent linkages that involve a thiol group and covalent linkage to active drugs D1 to Dn. A group Z is covalently linked to the carbonyl group of the branch units, and n is an integer greater than or equal to 4, with p and m selected from integers 1 through 8.
The patent further describes cleavable and non-cleavable linker options. The cleavable linker option includes a peptide linker having 2 to 20 amino acids and a polysulfide bond containing 2 to 8 sulfur atoms, and the active drugs include cytotoxic drugs such as tubulin inhibitors and DNA damaging agents.
Claims Coverage
The independent claims cover a branched antibody-drug conjugate with thiol-linked covalent attachment of multiple active drugs, where n is greater than or equal to 4 and p and m are selected from 1 to 8. The claims define A, Z, L1 to Ln+1, and D1 to Dn, and the dependent claims narrow linker cleavability, antibody formats, payload classes, and cancer-treatment use.
Branched thiol-linked antibody-drug conjugate with constrained p, m, and n
An antibody-drug conjugate represented by formula (I) to formula (IV), where A is an antibody or a functional binding fragment thereof, B1 to Bn are branch units, L1 is covalently linked to the amino terminus of B1, L2 to Ln+1 are covalently linked via a thiol group, D1 to Dn are each independently an active drug, Z is covalently linked to the carbonyl group of the branch units, n is an integer greater than or equal to 4, and p and m are selected from 1 to 8.
Linker-type selection for L2 to Ln+1
L2, L3, L4, and Ln+1 are selected from the linker options specified in the claim.
Cleavable linker option with peptide and polysulfide features
The cleavable linker includes a peptide linker of 2 to 20 amino acids and a polysulfide bond containing 2 to 8 sulfur atoms.
Non-cleavable linker option for L1 to Ln+1
Linker moieties L1, L2, L3, L4, and Ln+1 are non-cleavable linkers.
Defined antibody and antibody-fragment formats for A
A is selected from antibody and antibody-fragment types including Fab, Fab1-SH, F(ab1)2, Fv, single chain Fv, diabody, linear antibody, bispecific antibody, multispecific antibody, chimeric antibody, humanized antibody, fully human antibody, and fusion protein containing an antigen-binding fragment.
Active drug selection constrained to tubulin inhibitors and DNA damaging agents
The active drug is selected from tubulin inhibitors or DNA damaging agents, including dolastatins, auristatins, maytansines, calicheamicins, duocarmycins, pyrrolobenzodiazepines, camptothecins, and SN-38.
Cancer treatment use of the ADC
A method of treating cancer comprising administering an antibody-drug conjugate to a subject who needs such treatment.
The claims center on a branched antibody-drug conjugate with thiol-linked covalent attachment of multiple active drugs through L1 to Ln+1, with n greater than or equal to 4 and p and m selected from 1 to 8, and dependent claims further define linker options, antibody formats, payload classes, and cancer-treatment administration.
Stated Advantages
Enables a wider therapeutic window via broader drug selection including lower-toxicity drugs.
Improves uniformity at the same DAR by using multiple drugs per site.
Reduces the amount of antibody required and reduces cost.
Maintains antitumor efficacy using fewer coupled drugs versus single-drug-per-site ADCs.
Higher drug payload at limited binding sites.
Better uniformity at the same DAR.
Reduced antibody input/cost while maintaining tumor-killing potency with fewer drugs coupled per site.
Documented Applications
Treating cancer by administering the antibody-drug conjugate to a subject who needs such treatment.
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