An antibody-drug conjugate having two or more functional small molecule compounds for enhanced treatment of refractory diseases

An antibody drug conjugate with a branch functional small molecule having the Formula (I), (II), (III) (IV) represented as:

• D1 and D2 are a cytotoxic agent;
• mAb is an antibody or antibody like protein;
• n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20, and these numbers may have a decimal;
• L1, L2, La1, La2, Lb1, Lb2, Lc1, Lc2, Ld1, Ld2, Ld3, Ld4, Ld5, and Ld6 are a linker, which are independently selected from O, NH, S, N, NH—NH, N—N, N(R3), N(R3)N(R3′), C(═O)N, C(═O)NH, C(═O)N—N, C1-C8 of alkyl (alkylene);
• C2-C8 of heteroalkyl, alkylcycloalkyl, heterocycloalkyl;
• C3-C8 of aryl, Ar-alkyl, heterocyclic, carbocyclic, cycloalkyl, heteroalkylcycloalkyl, alkylcarbonyl, heteroaryl;
• or 1-8 carbon atoms of esters, ether, urea, carbamate, carbonate, thiourea, thioether, thiourea, amide, aminoalkylcarboxyl, thioalkylcarboxyl or oxylalkylcarboxyl;
• or 1-8 natural or unnatural amino acids;
• or polyethyleneoxy unit of formula (OCH2CH2)pOR3, or (OCH2CH(CH3))pOR3, or NH(CH2CH2O)pR3, or NH(CH2CH(CH3)O)pR3, or N[(CH2CH2O)pR3][(CH2CH2O)p,R3′], or (OCH2CH2)pCOOR3, or CH2CH2(OCH2CH2)pCOOR3, wherein p and p′ are independently an integer selected from 0 to about 100, or combination thereof;
• wherein R3 and R3, are independently H, C(═O)H, C(═O)CH3, C1-C8 of alkyl;
• or combination above thereof;
• wherein Lv1′ and Lv2′ are independently or jointly having the following structures:
• wherein “”is a site that links a drug or a site of linker Li or L2;
• “#” is a site that links a S (thiol), O (phenol), NH (amino), CHO (aldehyde), C(═O) (ketone), C(O)(NH) (amide) and C(O)(OH) (carboxylate) of an antibody;
• wherein R1 and R2 are H, C1-C6 of alkyl or a peptide containing 1-4 units of aminoacids;
• X, X1′ and X2′ are O, NH, S, CH2;
• the conneting bond “—” in the middle of the two atoms means it can link either one of the two atoms, Ar is an aromatic group;
• E1 and E2 are a joint group that link two reactivable groups, and are independently selected from CH, CH2, CH—CH, NH, NHNH, N(R3), N(R3)N(R3′), N═N, N—N, P, P(═O), S, Si, C2-C8 of alkyl, heteroalkyl, alkylcycloalkyl, heterocycloalkyl;
• C3-C8 of aryl, Ar-alkyl, heterocyclic, carbocyclic, cycloalkyl, heteroalkylcycloalkyl, alkylcarbonyl, heteroaryl;
• a peptide containing 1-4 units of aminoacids, or one of the following structures:
• wherein is the site of linkage;
• X1, X2, X3, X4, X5, or X6, are independently selected from NH;
• NHNH;
• N(R3);
• N(R3)N(R3′);
• O;
• S;
• C1-C6 of alkyl;
• R3 and R3′ are H, C1-C6 of alkyl;
• In addition, E1 can be absent, thus La1 or/and La2 can directly link to Lv1′ or Lv2′;
• m1, m2, m3, m4, m5, m6, m7, m8, m9, m10, m11 and m12 are independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 and these numbers may have a decimal;
• in addition, m2, m3, m8, m9 and/or m10 can be 0, thus Ld2—A2, Ld3 A3, Ld5—A5, and/or Ld6—A6 can be absent;
• A1, A2, A3, A4, A5 and A6 are independently a functional small molecule selected from (1) an affinity ligand:
• cell-penetrating peptide (CPP), including a ligand for bombesin receptor/neurotensin receptor or neuropeptide-Y receptor;
• (2) and/or a nucleoside antimetabolite/analog;
• which have either the synergy with D1 or D2, or enhanced affinity for mAb.