Use of Anti-her2 antibody-drug conjugate in treatment of biliary tract cancer

Abstract

The present disclosure pertains to the field of biomedicines and relates to use of an anti-HER2 antibody-drug conjugate in the treatment of biliary tract cancer. The present disclosure also relates to use of an anti-HER2 antibody-drug conjugate in the preparation of a medicament for treating biliary tract cancer in a subject. The present disclosure also relates to a method for treating biliary tract cancer in a subject, the method comprising administering an anti-HER2 antibody-drug conjugate to the subject. The method provides benefits for subjects with biliary tract cancer and has good safety.

Description

Use of anti-HER2 antibody drug conjugate in treating biliary tract cancer TECHNICAL FIELD

[0001] The present disclosure belongs to the field of biological medicine, and particularly relates to use of anti-HER2 antibody drug conjugate (ADC) in treating biliary tract cancer. BACKGROUND

[0002] Human epidermal growth factor receptor 2 (HER2) belongs to the human epidermal growth factor receptor family, which includes EGFR (ErbB-1), HER2 / c-neu (ErbB-2), HER3 (ErbB-3) and HER4 (ErbB-4), all of which are located on the cell surface and have similar structures. HER2, as a widely expressed receptor protein, abnormal gene amplification leads to overexpression of the protein, and further causes abnormal activation of the signal pathway, which is one of the main ways to promote the growth of solid tumors. HER2 can form homodimers, and is also prone to form heterodimers with other family receptors of HER, leading to phosphorylation of receptor tyrosine residues and starting multiple signal pathways including MPK, PI3K, JAK, STAT3, PKC, etc., thereby leading to cell proliferation and tumor occurrence.

[0003] Targeted therapy against HER2 is an important way to treat biliary tract cancer, and therefore there is an urgent need to explore drugs targeting HER2 to meet the huge demand for clinical treatment of biliary tract cancer. SUMMARY

[0004] Methods of treating biliary tract cancer

[0005] The present disclosure provides a method of treating biliary tract cancer in a subject, comprising administering to the subject an anti-HER2 antibody drug conjugate of the present disclosure. The present disclosure also provides a method of treating biliary tract cancer in a subject in the second line or more, comprising administering to the subject an anti-HER2 antibody drug conjugate of the present disclosure. In some embodiments, in the method, the anti-HER2 antibody drug conjugate is administered in a therapeutically effective amount.

[0006] The present disclosure also provides use of an anti-HER2 antibody drug conjugate of the present disclosure in the preparation of a medicament for treating biliary tract cancer in a subject. The present disclosure also provides use of an anti-HER2 antibody drug conjugate of the present disclosure in the preparation of a medicament for treating biliary tract cancer in a subject in the second line or more. In some embodiments, in the use, the medicament comprises a therapeutically effective amount of the anti-HER2 antibody drug conjugate.

[0007] The present disclosure also provides use of an anti-HER2 antibody drug conjugate of the present disclosure for treating a biliary tract cancer in a subject. The present disclosure also provides use of an anti-HER2 antibody drug conjugate of the present disclosure for second line or more line treatment of a biliary tract cancer in a subject. In some embodiments, the use, the anti-HER2 antibody drug conjugate is administered in a therapeutically effective amount.

[0008] The present disclosure also provides an anti-HER2 antibody drug conjugate of the present disclosure for treating a biliary tract cancer in a subject. The present disclosure also provides an anti-HER2 antibody drug conjugate of the present disclosure for second line or more line treatment of a biliary tract cancer in a subject. In some embodiments, the anti-HER2 antibody drug conjugate is administered in a therapeutically effective amount to a subject.

[0009] In some embodiments, in the method or use, the anti-HER2 antibody drug conjugate is administered once every 1 week (q1w), every 2 weeks (q2w), every 3 weeks (q3w), or every 4 weeks (q4w). In a particular embodiment, in the method or use, the anti-HER2 antibody drug conjugate is administered once every 3 weeks. In some embodiments, in the method or use, the anti-HER2 antibody drug conjugate is administered at a dose of 1.5-9 mg / kg, 4.5-7.5 mg / kg, 4.5-6 mg / kg, 5.4-7.5 mg / kg, or 6-7.5 mg / kg per dose. In some embodiments, in the method or use, the anti-HER2 antibody drug conjugate is administered at a dose of 1.5 mg / kg, 3 mg / kg, 4.5 mg / kg, 5.4 mg / kg, 6 mg / kg, 7.5 mg / kg, 9 mg / kg, or a dose within a range formed by any of the foregoing values, per dose. In some embodiments, in the method or use, the anti-HER2 antibody drug conjugate is administered at a dose of 6 mg / kg or 7.5 mg / kg per dose. In some embodiments, in the method or use, the anti-HER2 antibody drug conjugate is administered at a dose of 6 mg / kg per dose. In some embodiments, in the method or use, the anti-HER2 antibody drug conjugate is administered at a dose of 7.5 mg / kg per dose. In some embodiments, in the method or use, the anti-HER2 antibody drug conjugate is administered once every 1 week, every 2 weeks, every 3 weeks, or every 4 weeks, at a dose of 1.5-9 mg / kg, 4.5-7.5 mg / kg, 4.5-6 mg / kg, 5.4-7.5 mg / kg, or 6-7.5 mg / kg of the anti-HER2 antibody drug conjugate per dose. In some embodiments, in the method or use, the anti-HER2 antibody drug conjugate is administered once every 3 weeks, at a dose of 1.5 mg / kg, 3 mg / kg, 4.5 mg / kg, 5.4 mg / kg, 6 mg / kg, 7.5 mg / kg, or 9 mg / kg of the anti-HER2 antibody drug conjugate per dose. In some embodiments, in the method or use, the anti-HER2 antibody drug conjugate is administered once every 3 weeks, at a dose of 6 mg / kg or 7.5 mg / kg of the anti-HER2 antibody drug conjugate per dose. In some embodiments, in the method or use, the anti-HER2 antibody drug conjugate is administered once every 3 weeks, at a dose of 6 mg / kg of the anti-HER2 antibody drug conjugate per dose. In some embodiments, in the method or use, the anti-HER2 antibody drug conjugate is administered once every 3 weeks, at a dose of 7.5 mg / kg of the anti-HER2 antibody drug conjugate per dose.

[0010] In some embodiments, the method or use comprises one treatment cycle per 1 week, per 2 weeks, per 3 weeks, or per 4 weeks. In some embodiments, the method or use comprises one treatment cycle per 3 weeks. In some embodiments, the method or use comprises one treatment cycle per 1 week, per 2 weeks, per 3 weeks, or per 4 weeks, wherein the anti-HER2 antibody drug conjugate is administered once per treatment cycle. In some embodiments, the method or use comprises one treatment cycle per 3 weeks, wherein the anti-HER2 antibody drug conjugate is administered once per treatment cycle. In some embodiments, the method or use comprises one treatment cycle per 3 weeks, wherein 6 mg / kg or 7.5 mg / kg of the anti-HER2 antibody drug conjugate is administered per treatment cycle. In some embodiments, the method or use comprises one treatment cycle per 3 weeks, wherein 6 mg / kg or 7.5 mg / kg of the anti-HER2 antibody drug conjugate is administered on day 1 per treatment cycle. In some embodiments, the method or use comprises one treatment cycle per 3 weeks, wherein 6 mg / kg of the anti-HER2 antibody drug conjugate is administered per treatment cycle. In some embodiments, the method or use comprises one treatment cycle per 3 weeks, wherein 6 mg / kg of the anti-HER2 antibody drug conjugate is administered on day 1 per treatment cycle. In some embodiments, the method or use comprises one treatment cycle per 3 weeks, wherein 7.5 mg / kg of the anti-HER2 antibody drug conjugate is administered per treatment cycle. In some embodiments, the method or use comprises one treatment cycle per 3 weeks, wherein 7.5 mg / kg of the anti-HER2 antibody drug conjugate is administered on day 1 per treatment cycle.

[0011] The anti-HER2 antibody drug conjugate can be formulated together with one or more pharmaceutically acceptable excipients into a suitable pharmaceutical composition (or formulation). The pharmaceutical composition can be in a suitable dosage form. In some embodiments, the anti-HER2 antibody drug conjugate is formulated into a formulation for parenteral route of administration. In some specific embodiments, the anti-HER2 antibody drug conjugate is formulated into a formulation for intravenous or intramuscular administration. In some specific embodiments, the anti-HER2 antibody drug conjugate can be formulated into an injection. In some specific embodiments, the anti-HER2 antibody drug conjugate is formulated into a formulation for intravenous injection or infusion.

[0012] In some embodiments, in the method or use, the administration of the anti-HER2 antibody drug conjugate is performed using intravenous infusion.

[0013] In some embodiments, the biliary tract cancer is unresectable, refractory, advanced, recurrent, and / or metastatic biliary tract cancer. In some embodiments, the biliary tract cancer is unresectable biliary tract cancer. In some embodiments, the biliary tract cancer is refractory biliary tract cancer. In some embodiments, the biliary tract cancer is advanced biliary tract cancer. In some embodiments, the biliary tract cancer is locally advanced biliary tract cancer. In some embodiments, the biliary tract cancer is recurrent and / or metastatic biliary tract cancer. In some embodiments, the biliary tract cancer is recurrent biliary tract cancer. In some embodiments, the biliary tract cancer is metastatic biliary tract cancer. In some embodiments, the biliary tract cancer is unresectable locally advanced biliary tract cancer. In some embodiments, the biliary tract cancer is unresectable recurrent and / or metastatic biliary tract cancer. In some embodiments, the biliary tract cancer is unresectable metastatic biliary tract cancer. In some embodiments, the biliary tract cancer is unresectable locally advanced, recurrent, and / or metastatic biliary tract cancer. In some embodiments, the biliary tract cancer is unresectable locally advanced and / or metastatic biliary tract cancer.

[0014] In some embodiments, the biliary tract cancer is cholangiocarcinoma. In some embodiments, the cholangiocarcinoma is unresectable, refractory, advanced, recurrent, and / or metastatic cholangiocarcinoma. In some embodiments, the cholangiocarcinoma is unresectable cholangiocarcinoma. In some embodiments, the cholangiocarcinoma is refractory cholangiocarcinoma. In some embodiments, the cholangiocarcinoma is advanced cholangiocarcinoma. In some embodiments, the cholangiocarcinoma is locally advanced cholangiocarcinoma. In some embodiments, the cholangiocarcinoma is recurrent and / or metastatic cholangiocarcinoma. In some embodiments, the cholangiocarcinoma is recurrent cholangiocarcinoma. In some embodiments, the cholangiocarcinoma is metastatic cholangiocarcinoma. In some embodiments, the cholangiocarcinoma is unresectable locally advanced cholangiocarcinoma. In some embodiments, the cholangiocarcinoma is unresectable recurrent and / or metastatic cholangiocarcinoma. In some embodiments, the cholangiocarcinoma is unresectable metastatic cholangiocarcinoma. In some embodiments, the cholangiocarcinoma is unresectable locally advanced, recurrent, and / or metastatic cholangiocarcinoma. In some embodiments, the cholangiocarcinoma is unresectable locally advanced and / or metastatic cholangiocarcinoma.

[0015] In some embodiments, the biliary tract cancer is intrahepatic cholangiocarcinoma (iCCA). In some embodiments, the intrahepatic cholangiocarcinoma is unresectable, refractory, advanced, recurrent, and / or metastatic intrahepatic cholangiocarcinoma. In some embodiments, the intrahepatic cholangiocarcinoma is unresectable intrahepatic cholangiocarcinoma. In some embodiments, the intrahepatic cholangiocarcinoma is refractory intrahepatic cholangiocarcinoma. In some embodiments, the intrahepatic cholangiocarcinoma is advanced intrahepatic cholangiocarcinoma. In some embodiments, the intrahepatic cholangiocarcinoma is locally advanced intrahepatic cholangiocarcinoma. In some embodiments, the intrahepatic cholangiocarcinoma is recurrent and / or metastatic intrahepatic cholangiocarcinoma. In some embodiments, the intrahepatic cholangiocarcinoma is recurrent intrahepatic cholangiocarcinoma. In some embodiments, the intrahepatic cholangiocarcinoma is metastatic intrahepatic cholangiocarcinoma. In some embodiments, the intrahepatic cholangiocarcinoma is unresectable locally advanced intrahepatic cholangiocarcinoma. In some embodiments, the intrahepatic cholangiocarcinoma is unresectable recurrent and / or metastatic intrahepatic cholangiocarcinoma. In some embodiments, the intrahepatic cholangiocarcinoma is unresectable metastatic intrahepatic cholangiocarcinoma. In some embodiments, the intrahepatic cholangiocarcinoma is unresectable locally advanced, recurrent, and / or metastatic intrahepatic cholangiocarcinoma. In some embodiments, the intrahepatic cholangiocarcinoma is unresectable locally advanced and / or metastatic intrahepatic cholangiocarcinoma.

[0016] In some embodiments, the biliary tract cancer is perihilar cholangiocarcinoma (pCCA). In some embodiments, the perihilar cholangiocarcinoma is unresectable, refractory, advanced, recurrent, and / or metastatic perihilar cholangiocarcinoma. In some embodiments, the perihilar cholangiocarcinoma is unresectable perihilar cholangiocarcinoma. In some embodiments, the perihilar cholangiocarcinoma is refractory perihilar cholangiocarcinoma. In some embodiments, the perihilar cholangiocarcinoma is advanced perihilar cholangiocarcinoma. In some embodiments, the perihilar cholangiocarcinoma is locally advanced perihilar cholangiocarcinoma. In some embodiments, the perihilar cholangiocarcinoma is recurrent and / or metastatic perihilar cholangiocarcinoma. In some embodiments, the perihilar cholangiocarcinoma is recurrent perihilar cholangiocarcinoma. In some embodiments, the perihilar cholangiocarcinoma is metastatic perihilar cholangiocarcinoma. In some embodiments, the perihilar cholangiocarcinoma is unresectable locally advanced perihilar cholangiocarcinoma. In some embodiments, the perihilar cholangiocarcinoma is unresectable recurrent and / or metastatic perihilar cholangiocarcinoma. In some embodiments, the perihilar cholangiocarcinoma is unresectable metastatic perihilar cholangiocarcinoma. In some embodiments, the perihilar cholangiocarcinoma is unresectable locally advanced, recurrent, and / or metastatic perihilar cholangiocarcinoma. In some embodiments, the perihilar cholangiocarcinoma is unresectable locally advanced and / or metastatic perihilar cholangiocarcinoma.

[0017] In some embodiments, the biliary tract cancer is distal cholangiocarcinoma (dCCA). In some embodiments, the distal cholangiocarcinoma is unresectable, refractory, advanced, recurrent, and / or metastatic distal cholangiocarcinoma. In some embodiments, the distal cholangiocarcinoma is unresectable distal cholangiocarcinoma. In some embodiments, the distal cholangiocarcinoma is refractory distal cholangiocarcinoma. In some embodiments, the distal cholangiocarcinoma is advanced distal cholangiocarcinoma. In some embodiments, the distal cholangiocarcinoma is locally advanced distal cholangiocarcinoma. In some embodiments, the distal cholangiocarcinoma is recurrent and / or metastatic distal cholangiocarcinoma. In some embodiments, the distal cholangiocarcinoma is recurrent distal cholangiocarcinoma. In some embodiments, the distal cholangiocarcinoma is metastatic distal cholangiocarcinoma. In some embodiments, the distal cholangiocarcinoma is unresectable locally advanced distal cholangiocarcinoma. In some embodiments, the distal cholangiocarcinoma is unresectable recurrent and / or metastatic distal cholangiocarcinoma. In some embodiments, the distal cholangiocarcinoma is unresectable metastatic distal cholangiocarcinoma. In some embodiments, the distal cholangiocarcinoma is unresectable locally advanced, recurrent, and / or metastatic distal cholangiocarcinoma. In some embodiments, the distal cholangiocarcinoma is unresectable locally advanced and / or metastatic distal cholangiocarcinoma.

[0018] In some embodiments, the biliary tract cancer is gallbladder cancer (GBC). In some embodiments, the gallbladder cancer is unresectable, refractory, advanced, recurrent, and / or metastatic gallbladder cancer. In some embodiments, the gallbladder cancer is unresectable gallbladder cancer. In some embodiments, the gallbladder cancer is refractory gallbladder cancer. In some embodiments, the gallbladder cancer is advanced gallbladder cancer. In some embodiments, the gallbladder cancer is locally advanced gallbladder cancer. In some embodiments, the gallbladder cancer is recurrent and / or metastatic gallbladder cancer. In some embodiments, the gallbladder cancer is recurrent gallbladder cancer. In some embodiments, the gallbladder cancer is metastatic gallbladder cancer. In some embodiments, the gallbladder cancer is unresectable locally advanced gallbladder cancer. In some embodiments, the gallbladder cancer is unresectable recurrent and / or metastatic gallbladder cancer. In some embodiments, the gallbladder cancer is unresectable metastatic gallbladder cancer. In some embodiments, the gallbladder cancer is unresectable locally advanced, recurrent, and / or metastatic gallbladder cancer. In some embodiments, the gallbladder cancer is unresectable locally advanced and / or metastatic gallbladder cancer.

[0019] In some embodiments, the biliary tract cancer is a HER2-expressing biliary tract cancer. In some embodiments, the biliary tract cancer is a HER2-amplified biliary tract cancer. In some embodiments, the biliary tract cancer is a HER2-mutated biliary tract cancer. In some embodiments, the biliary tract cancer is a HER2-expressing, -amplified, or -mutated biliary tract cancer. In some embodiments, the biliary tract cancer is a HER2-positive biliary tract cancer. In some embodiments, the HER2-positive biliary tract cancer is a biliary tract cancer in which the expression of HER2 is determined to be 3+ by immunohistochemistry (IHC) (i.e., IHC 3+). In some embodiments, the HER2-positive biliary tract cancer is a biliary tract cancer in which the expression of HER2 is determined to be 2+ by IHC and positive by ISH (i.e., IHC 2+ and ISH+).

[0020] In some embodiments, the biliary tract cancer is a HER2-expressing biliary tract cancer. In some embodiments, the biliary tract cancer is a HER2-amplified biliary tract cancer. In some embodiments, the biliary tract cancer is a HER2-mutated biliary tract cancer. In some embodiments, the biliary tract cancer is a HER2-expressing, -amplified, or -mutated biliary tract cancer. In some embodiments, the biliary tract cancer is a HER2-positive biliary tract cancer. In some embodiments, the HER2-positive biliary tract cancer is a biliary tract cancer in which the expression of HER2 is determined to be 3+ by immunohistochemistry (IHC) (i.e., IHC 3+). In some embodiments, the HER2-positive biliary tract cancer is a biliary tract cancer in which the expression of HER2 is determined to be 2+ by IHC and positive by ISH (i.e., IHC 2+ and ISH+).

[0021] In some embodiments, the biliary tract cancer is a HER2-expressing biliary tract cancer. In some embodiments, the biliary tract cancer is a HER2-amplified biliary tract cancer. In some embodiments, the biliary tract cancer is a HER2-mutated biliary tract cancer. In some embodiments, the biliary tract cancer is a HER2-expressing, -amplified, or -mutated biliary tract cancer. In some embodiments, the biliary tract cancer is a HER2-positive biliary tract cancer. In some embodiments, the HER2-positive biliary tract cancer is a biliary tract cancer in which the expression of HER2 is determined to be 3+ by immunohistochemistry (IHC) (i.e., IHC 3+). In some embodiments, the HER2-positive biliary tract cancer is a biliary tract cancer in which the expression of HER2 is determined to be 2+ by IHC and positive by ISH (i.e., IHC 2+ and ISH+).

[0022] In some embodiments, the biliary tract cancer is hilar cholangiocarcinoma. In some embodiments, the hilar cholangiocarcinoma is HER2-expressing hilar cholangiocarcinoma. In some embodiments, the hilar cholangiocarcinoma is HER2-amplified hilar cholangiocarcinoma. In some embodiments, the hilar cholangiocarcinoma is HER2-mutated hilar cholangiocarcinoma. In some embodiments, the hilar cholangiocarcinoma is HER2-expressing, -amplified, or -mutated hilar cholangiocarcinoma. In some embodiments, the hilar cholangiocarcinoma is HER2-positive hilar cholangiocarcinoma. In some embodiments, the HER2-positive hilar cholangiocarcinoma is a hilar cholangiocarcinoma in which the expression of HER2 is determined to be 3+ by immunohistochemistry (IHC). In some embodiments, the HER2-positive hilar cholangiocarcinoma is a hilar cholangiocarcinoma in which the expression of HER2 is determined to be 2+ by IHC and the expression of HER2 is determined to be positive by ISH.

[0023] In some embodiments, the biliary tract cancer is distal cholangiocarcinoma. In some embodiments, the distal cholangiocarcinoma is HER2-expressing distal cholangiocarcinoma. In some embodiments, the distal cholangiocarcinoma is HER2-amplified distal cholangiocarcinoma. In some embodiments, the distal cholangiocarcinoma is HER2-mutated distal cholangiocarcinoma. In some embodiments, the distal cholangiocarcinoma is HER2-expressing, -amplified, or -mutated distal cholangiocarcinoma. In some embodiments, the distal cholangiocarcinoma is HER2-positive distal cholangiocarcinoma. In some embodiments, the HER2-positive distal cholangiocarcinoma is a distal cholangiocarcinoma in which the expression of HER2 is determined to be 3+ by immunohistochemistry (IHC). In some embodiments, the HER2-positive distal cholangiocarcinoma is a distal cholangiocarcinoma in which the expression of HER2 is determined to be 2+ by IHC and the expression of HER2 is determined to be positive by ISH.

[0024] In some embodiments, the biliary tract cancer is distal cholangiocarcinoma. In some embodiments, the distal cholangiocarcinoma is HER2-expressing distal cholangiocarcinoma. In some embodiments, the distal cholangiocarcinoma is HER2-amplified distal cholangiocarcinoma. In some embodiments, the distal cholangiocarcinoma is HER2-mutated distal cholangiocarcinoma. In some embodiments, the distal cholangiocarcinoma is HER2-expressing, -amplified, or -mutated distal cholangiocarcinoma. In some embodiments, the distal cholangiocarcinoma is HER2-positive distal cholangiocarcinoma. In some embodiments, the HER2-positive distal cholangiocarcinoma is a distal cholangiocarcinoma in which the expression of HER2 is determined to be 3+ by immunohistochemistry (IHC). In some embodiments, the HER2-positive distal cholangiocarcinoma is a distal cholangiocarcinoma in which the expression of HER2 is determined to be 2+ by IHC and the expression of HER2 is determined to be positive by ISH.

[0025] In some embodiments, the HER2 mutation is at least one selected from the group consisting of Y772_A775dup, G778_P780dup, G776delinsVC, E770_A771insAYVM, A771_Y772insYVMA, M774_A775insAYVM, G776delinsLC, G776delinsAVGC, G776delinsVV, G776_V777insL, G776_V777insVC, G776_V777insVGC, V777_G778insCG, V777_G778insG, G778_S779insG, S779_P780insVGS, L755S, V777L, V659E, G660D, S310F, A20T, A21S, R143Q, K200N, A242V, D277Y, A293P, N302K, V308M, S310Y, N319Y, S335C, R340P, S418T, W452C, V541M, I613V, P627H, A644V, R647G, I654V, I655V, I661V, R678Q, Q680H, V697L, G704R, Q709L, Q711H, G727A, T733I, E744G, N745D, L755P, L755A, L755F, S760F, D769H, D769N, D769Y, G776C, G776L, S779P, R784C, R784H, L785R, L786V, T791I, G804S, L807F, S819F, I829T, V842I, L846F, T862I, R868W, L869R, T875I, W906*, T917S, Q943*, S1007*, and S1151L. In some embodiments, the HER2 mutation is at least one selected from the group consisting of Y772_A775dup, G778_P780dup, G776delinsVC, L755S, V777L, V659E, G660D, and S310F. In some embodiments, the HER2 mutation is an exon 20 insertion mutation.In some embodiments, the HER2 mutation is at least one selected from the group consisting of Y772_A775dup, G778_P780dup, G776delinsVC, E770_A771insAYVM, A771_Y772insYVMA, M774_A775insAYVM, G776delinsLC, G776delinsAVGC, G776delinsVV, G776_V777insL, G776_V777insVC, G776_V777insVGC, V777_G778insCG, V777_G778insG, G778_S779insG, and S779_P780insVGS. In some embodiments, the HER2 mutation is at least one selected from the group consisting of Y772_A775dup, G778_P780dup, and G776delinsVC. In some embodiments, the HER2 mutation is a single base pair substitution mutation. In some embodiments, the HER2 mutation is at least one selected from the group consisting of L755S, V777L, V659E, G660D, S310F, A20T, A21S, R143Q, K200N, A242V, D277Y, A293P, N302K, V308M, S310Y, N319Y, S335C, R340P, S418T, W452C, V541M, I613V, P627H, A644V, R647G, I654V, I655V, I661V, R678Q, Q680H, V697L, G704R, Q709L, Q711H, G727A, T733I, E744G, N745D, L755P, L755A, L755F, S760F, D769H, D769N, D769Y, G776C, G776L, S779P, R784C, R784H, L785R, L786V, T791I, G804S, L807F, S819F, I829T, V842I, L846F, T862I, R868W, L869R, T875I, W906*, T917S, Q943*, S1007*, and S1151L. In some embodiments, the HER2 mutation is at least one selected from the group consisting of L755S, V777L, V659E, G660D, and S310F.

[0026] In some embodiments, the biliary tract cancer is a FGFR2 fusion biliary tract cancer. In some embodiments, the biliary tract cancer is an IDH1 / 2 mutant biliary tract cancer. In some embodiments, the biliary tract cancer is an IDH1 mutant biliary tract cancer. In some embodiments, the biliary tract cancer is a BRAF mutant biliary tract cancer. In some embodiments, the biliary tract cancer is a BRAF V600E mutant biliary tract cancer. In some embodiments, the biliary tract cancer is a NTRK1-3 fusion biliary tract cancer. In some embodiments, the biliary tract cancer is a NTRK1-3 rearrangement biliary tract cancer. In some embodiments, the biliary tract cancer is a RET fusion biliary tract cancer. In some embodiments, the biliary tract cancer is a RET rearrangement biliary tract cancer. In some embodiments, the biliary tract cancer is a TP53 mutant biliary tract cancer. In some embodiments, the biliary tract cancer is a KRAS mutant biliary tract cancer. In some embodiments, the biliary tract cancer is a BRCA1 mutant biliary tract cancer.

[0027] In some embodiments, the biliary tract cancer is a HER2-positive unresectable biliary tract cancer. In some embodiments, the biliary tract cancer is a HER2-positive advanced biliary tract cancer. In some embodiments, the biliary tract cancer is a HER2-positive locally advanced biliary tract cancer. In some embodiments, the biliary tract cancer is a HER2-positive recurrent and / or metastatic biliary tract cancer. In some embodiments, the biliary tract cancer is a HER2-positive recurrent biliary tract cancer. In some embodiments, the biliary tract cancer is a HER2-positive metastatic biliary tract cancer. In some embodiments, the biliary tract cancer is a HER2-positive unresectable locally advanced, recurrent, and / or metastatic biliary tract cancer. In some embodiments, the biliary tract cancer is a HER2-positive unresectable locally advanced and / or metastatic biliary tract cancer.

[0028] In some embodiments, the biliary tract cancer is a HER2-positive unresectable biliary tract cancer. In some embodiments, the biliary tract cancer is a HER2-positive advanced biliary tract cancer. In some embodiments, the biliary tract cancer is a HER2-positive locally advanced biliary tract cancer. In some embodiments, the biliary tract cancer is a HER2-positive recurrent and / or metastatic biliary tract cancer. In some embodiments, the biliary tract cancer is a HER2-positive recurrent biliary tract cancer. In some embodiments, the biliary tract cancer is a HER2-positive metastatic biliary tract cancer. In some embodiments, the biliary tract cancer is a HER2-positive unresectable locally advanced, recurrent, and / or metastatic biliary tract cancer. In some embodiments, the biliary tract cancer is a HER2-positive unresectable locally advanced and / or metastatic biliary tract cancer.

[0029] In some embodiments, the biliary tract cancer is intrahepatic cholangiocarcinoma. In some embodiments, the intrahepatic cholangiocarcinoma is HER2-positive unresectable intrahepatic cholangiocarcinoma. In some embodiments, the intrahepatic cholangiocarcinoma is HER2-positive advanced intrahepatic cholangiocarcinoma. In some embodiments, the intrahepatic cholangiocarcinoma is HER2-positive locally advanced intrahepatic cholangiocarcinoma. In some embodiments, the intrahepatic cholangiocarcinoma is HER2-positive recurrent and / or metastatic intrahepatic cholangiocarcinoma. In some embodiments, the intrahepatic cholangiocarcinoma is HER2-positive recurrent intrahepatic cholangiocarcinoma. In some embodiments, the intrahepatic cholangiocarcinoma is HER2-positive metastatic intrahepatic cholangiocarcinoma. In some embodiments, the intrahepatic cholangiocarcinoma is HER2-positive unresectable locally advanced, recurrent and / or metastatic intrahepatic cholangiocarcinoma. In some embodiments, the intrahepatic cholangiocarcinoma is HER2-positive unresectable locally advanced and / or metastatic intrahepatic cholangiocarcinoma.

[0030] In some embodiments, the biliary tract cancer is hilar cholangiocarcinoma. In some embodiments, the hilar cholangiocarcinoma is HER2-positive unresectable hilar cholangiocarcinoma. In some embodiments, the hilar cholangiocarcinoma is HER2-positive advanced hilar cholangiocarcinoma. In some embodiments, the hilar cholangiocarcinoma is HER2-positive locally advanced hilar cholangiocarcinoma. In some embodiments, the hilar cholangiocarcinoma is HER2-positive recurrent and / or metastatic hilar cholangiocarcinoma. In some embodiments, the hilar cholangiocarcinoma is HER2-positive recurrent hilar cholangiocarcinoma. In some embodiments, the hilar cholangiocarcinoma is HER2-positive metastatic hilar cholangiocarcinoma. In some embodiments, the hilar cholangiocarcinoma is HER2-positive unresectable locally advanced, recurrent and / or metastatic hilar cholangiocarcinoma. In some embodiments, the hilar cholangiocarcinoma is HER2-positive unresectable locally advanced and / or metastatic hilar cholangiocarcinoma.

[0031] In some embodiments, the biliary tract cancer is distal bile duct cancer. In some embodiments, the distal bile duct cancer is HER2-positive unresectable distal bile duct cancer. In some embodiments, the distal bile duct cancer is HER2-positive advanced distal bile duct cancer. In some embodiments, the distal bile duct cancer is HER2-positive locally advanced distal bile duct cancer. In some embodiments, the distal bile duct cancer is HER2-positive recurrent and / or metastatic distal bile duct cancer. In some embodiments, the distal bile duct cancer is HER2-positive recurrent distal bile duct cancer. In some embodiments, the distal bile duct cancer is HER2-positive metastatic distal bile duct cancer. In some embodiments, the distal bile duct cancer is HER2-positive unresectable locally advanced, recurrent, and / or metastatic distal bile duct cancer. In some embodiments, the distal bile duct cancer is HER2-positive unresectable locally advanced and / or metastatic distal bile duct cancer.

[0032] In some embodiments, the biliary tract cancer is gallbladder cancer. In some embodiments, the gallbladder cancer is HER2-positive unresectable gallbladder cancer. In some embodiments, the gallbladder cancer is HER2-positive advanced gallbladder cancer. In some embodiments, the gallbladder cancer is HER2-positive locally advanced gallbladder cancer. In some embodiments, the gallbladder cancer is HER2-positive recurrent and / or metastatic gallbladder cancer. In some embodiments, the gallbladder cancer is HER2-positive recurrent gallbladder cancer. In some embodiments, the gallbladder cancer is HER2-positive metastatic gallbladder cancer. In some embodiments, the gallbladder cancer is HER2-positive unresectable locally advanced, recurrent, and / or metastatic gallbladder cancer. In some embodiments, the gallbladder cancer is HER2-positive unresectable locally advanced and / or metastatic gallbladder cancer.

[0033] In some embodiments, the subject with the biliary tract cancer has been previously treated for the biliary tract cancer (e.g., failed or was intolerant to treatment). In some embodiments, the subject with the biliary tract cancer has been previously treated with at least one line of therapy for the biliary tract cancer (e.g., failed or was intolerant to treatment). In some embodiments, the subject with the biliary tract cancer has been previously treated with at least one line of chemotherapy for the biliary tract cancer (e.g., failed or was intolerant to treatment).

[0034] In some embodiments, the biliary tract cancer is gallbladder cancer. In some embodiments, the gallbladder cancer is HER2-positive unresectable gallbladder cancer. In some embodiments, the gallbladder cancer is HER2-positive advanced gallbladder cancer. In some embodiments, the gallbladder cancer is HER2-positive locally advanced gallbladder cancer. In some embodiments, the gallbladder cancer is HER2-positive recurrent and / or metastatic gallbladder cancer. In some embodiments, the gallbladder cancer is HER2-positive recurrent gallbladder cancer. In some embodiments, the gallbladder cancer is HER2-positive metastatic gallbladder cancer. In some embodiments, the gallbladder cancer is HER2-positive unresectable locally advanced, recurrent, and / or metastatic gallbladder cancer. In some embodiments, the gallbladder cancer is HER2-positive unresectable locally advanced and / or metastatic gallbladder cancer.

[0035] In some embodiments, the biliary tract cancer is intrahepatic cholangiocarcinoma. In some embodiments, the subject with intrahepatic cholangiocarcinoma has been previously treated for intrahepatic cholangiocarcinoma (e.g., failed or was intolerant to treatment). In some embodiments, the subject with intrahepatic cholangiocarcinoma has been previously treated with at least one line of therapy for intrahepatic cholangiocarcinoma (e.g., failed or was intolerant to treatment). In some embodiments, the subject with intrahepatic cholangiocarcinoma has been previously treated with at least one line of chemotherapy for intrahepatic cholangiocarcinoma (e.g., failed or was intolerant to treatment).

[0036] In some embodiments, the biliary tract cancer is hilar cholangiocarcinoma. In some embodiments, the subject with hilar cholangiocarcinoma has been previously treated for hilar cholangiocarcinoma (e.g., failed or was intolerant to treatment). In some embodiments, the subject with hilar cholangiocarcinoma has been previously treated with at least one line of therapy for hilar cholangiocarcinoma (e.g., failed or was intolerant to treatment). In some embodiments, the subject with hilar cholangiocarcinoma has been previously treated with at least one line of chemotherapy for hilar cholangiocarcinoma (e.g., failed or was intolerant to treatment).

[0037] In some embodiments, the biliary tract cancer is distal cholangiocarcinoma. In some embodiments, the subject with distal cholangiocarcinoma has been previously treated for distal cholangiocarcinoma (e.g., failed or was intolerant to treatment). In some embodiments, the subject with distal cholangiocarcinoma has been previously treated with at least one line of therapy for distal cholangiocarcinoma (e.g., failed or was intolerant to treatment). In some embodiments, the subject with distal cholangiocarcinoma has been previously treated with at least one line of chemotherapy for distal cholangiocarcinoma (e.g., failed or was intolerant to treatment).

[0038] In some embodiments, the biliary tract cancer is gallbladder cancer. In some embodiments, the subject with gallbladder cancer has been previously treated for gallbladder cancer (e.g., failed or was intolerant to treatment). In some embodiments, the subject with gallbladder cancer has been previously treated with at least one line of therapy for gallbladder cancer (e.g., failed or was intolerant to treatment). In some embodiments, the subject with gallbladder cancer has been previously treated with at least one line of chemotherapy for gallbladder cancer (e.g., failed or was intolerant to treatment).

[0039] In some embodiments, the subject with biliary tract cancer has previously received gemcitabine, a platinum drug, and / or a fluorouracil drug for treatment of biliary tract cancer (e.g., failed treatment or was intolerant). In some embodiments, the subject with cholangiocarcinoma has previously received gemcitabine, a platinum drug, and / or a fluorouracil drug for treatment of cholangiocarcinoma (e.g., failed treatment or was intolerant). In some embodiments, the subject is one who has failed at least one line of chemotherapy with a gemcitabine, platinum, or fluorouracil-based monotherapy or combination chemotherapy regimen. In some embodiments, the subject with intrahepatic cholangiocarcinoma has previously received gemcitabine, a platinum drug, and / or a fluorouracil drug for treatment of intrahepatic cholangiocarcinoma (e.g., failed treatment or was intolerant). In some embodiments, the subject with perihilar cholangiocarcinoma has previously received gemcitabine, a platinum drug, and / or a fluorouracil drug for treatment of perihilar cholangiocarcinoma (e.g., failed treatment or was intolerant). In some embodiments, the subject with distal cholangiocarcinoma has previously received gemcitabine, a platinum drug, and / or a fluorouracil drug for treatment of distal cholangiocarcinoma (e.g., failed treatment or was intolerant). In some embodiments, the subject with gallbladder cancer has previously received gemcitabine, a platinum drug, and / or a fluorouracil drug for treatment of gallbladder cancer (e.g., failed treatment or was intolerant). The platinum drug includes, but is not limited to, oxaliplatin, cisplatin. The fluorouracil drug includes, but is not limited to, 5-fluorouracil, capecitabine, tegafur.

[0040] Anti-HER2 antibody drug conjugate

[0041] The anti-HER2 antibody drug conjugate used in the present disclosure is linked by a drug-linker of the structure shown in Formula la,

[0042] wherein,

[0043] the 3-position (i.e., the position of attachment) of -(succinimid-3-yl-N)- in Formula la is attached to the antigen-binding construct targeting HER2,

[0044] ​The antigen binding construct targeting HER2 comprises a first antigen binding fragment comprising a heavy chain CDR1 (HCDR1) comprising the amino acid sequence set forth in SEQ ID NO: 1, a HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 2, a HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 3, a light chain CDR1 (LCDR1) comprising the amino acid sequence set forth in SEQ ID NO: 4, a LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 5, and a LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 6, and a second antigen binding fragment comprising a HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 9, a HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 10, a HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 11, a LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 13, and a LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 14.

[0045] In some embodiments, the 3-position of the -(succinimid-3-yl-N)- is linked to the antigen binding construct targeting HER2 via a thioether linkage.

[0046] In some embodiments, the average number of drug-linker per each antigen binding construct targeting HER2 in the anti-HER2 antibody drug conjugate is 2 to 8. In some embodiments, the average number of drug-linker per each antigen binding construct targeting HER2 in the anti-HER2 antibody drug conjugate is 4 to 7. In some embodiments, the average number of drug-linker per each antigen binding construct targeting HER2 in the anti-HER2 antibody drug conjugate is 5 to 6. In some embodiments, the average number of drug-linker per each antigen binding construct targeting HER2 in the anti-HER2 antibody drug conjugate is 5.5 to 6. In some embodiments, the average number of drug-linker per each antigen binding construct targeting HER2 in the anti-HER2 antibody drug conjugate is 5.8 to 6.

[0047] Table 1. Exemplary CDR sequences of the antigen binding construct targeting HER2

[0048] It will be understood by one of skill in the art that the term "CDR" or "complementarity determining region" of a given antigen binding fragment or region thereof (e.g., variable region) is understood to encompass complementarity determining regions as defined by any one of the known schemes, unless otherwise specified. While the CDRs claimed in the present disclosure are based on the sequences set forth in Table 1 (one definition), the corresponding amino acid sequences according to other rules of CDR definition (e.g., one or several of the definitions well known in the art such as AbM, CCG, Kabat, Chothia, IMGT, or Contact) should also fall within the scope of the present disclosure.

[0049] In some embodiments, the first antigen binding fragment comprises a heavy chain variable region having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 7. In some embodiments, the first antigen binding fragment comprises a light chain variable region having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 8. In some embodiments, the first antigen binding fragment comprises a heavy chain variable region having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 7, and a light chain variable region having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 8. In some embodiments, the first antigen binding fragment comprises a heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 7, and a light chain variable region having the amino acid sequence set forth in SEQ ID NO: 8. In some particular embodiments, the amino acid sequence of the heavy chain variable region of the first antigen binding fragment is set forth in SEQ ID NO: 7, and the amino acid sequence of the light chain variable region is set forth in SEQ ID NO: 8.

[0050] In some embodiments, the first antigen binding fragment comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises a HCDR1 having the amino acid sequence set forth in SEQ ID NO: 1, a HCDR2 having the amino acid sequence set forth in SEQ ID NO: 2, and a HCDR3 having the amino acid sequence set forth in SEQ ID NO: 3, the light chain variable region comprises a LCDR1 having the amino acid sequence set forth in SEQ ID NO: 4, a LCDR2 having the amino acid sequence set forth in SEQ ID NO: 5, and a LCDR3 having the amino acid sequence set forth in SEQ ID NO: 6, and the heavy chain variable region comprises an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 7, and the light chain variable region comprises an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 8.

[0051] In some embodiments, the difference amino acid in the amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 7 or SEQ ID NO: 8 is located in a FR region.

[0052] In some embodiments, the second antigen binding fragment comprises a heavy chain variable region having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 15. In some embodiments, the second antigen binding fragment comprises a light chain variable region having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 16. In some embodiments, the second antigen binding fragment comprises a heavy chain variable region having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 15, and a light chain variable region having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 16. In some embodiments, the second antigen binding fragment comprises a heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 15, and a light chain variable region having the amino acid sequence set forth in SEQ ID NO: 16. In some particular embodiments, the amino acid sequence of the heavy chain variable region of the second antigen binding fragment is set forth in SEQ ID NO: 15, and the amino acid sequence of the light chain variable region is set forth in SEQ ID NO: 16.

[0053] In some embodiments, the second antigen binding fragment comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises a HCDR1 having the amino acid sequence set forth in SEQ ID NO: 9, a HCDR2 having the amino acid sequence set forth in SEQ ID NO: 10, and a HCDR3 having the amino acid sequence set forth in SEQ ID NO: 11, the light chain variable region comprises a LCDR1 having the amino acid sequence set forth in SEQ ID NO: 12, a LCDR2 having the amino acid sequence set forth in SEQ ID NO: 13, and a LCDR3 having the amino acid sequence set forth in SEQ ID NO: 14, and the heavy chain variable region comprises an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 15, and the light chain variable region comprises an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 16.

[0054] In some embodiments, the difference amino acid in the amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 15 or SEQ ID NO: 16 is located in a FR region.

[0055] In some embodiments, the antigen binding construct targeting HER2 can further comprise a constant region of an immunoglobulin, or a fragment, analog, variant or derivative of the constant region. In some embodiments, the constant region comprises a heavy chain constant region and a light chain constant region. In some embodiments, the heavy chain constant region is from a human immunoglobulin heavy chain, such as a heavy chain of an IgGl, IgG2, IgG3 and IgG4 or other class of immunoglobulin, preferably a heavy chain of IgGl. In some embodiments, the light chain constant region is from a human immunoglobulin light chain, such as a kappa light chain or lambda light chain of a human immunoglobulin. In some embodiments, the constant region can comprise any modification described in the text, such as insertion, deletion, substitution or chemical modification of an amino acid. In some embodiments, the C-terminal lysine of the heavy chain constant region can be present or absent, the absence of the C-terminal lysine of the heavy chain constant region typically occurs during recombinant expression. In some embodiments, the constant region comprises a mutation that alters effector function. In some embodiments, any amino acid residue of the constant region can be substituted with an amino acid residue of any allotype.

[0056] In some embodiments, the antigen binding construct targeting HER2 comprises a first polypeptide chain having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 17. In some embodiments, the antigen binding construct targeting HER2 comprises a second polypeptide chain having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 18. In some embodiments, the antigen binding construct targeting HER2 comprises a third polypeptide chain having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 19. In some embodiments, the antigen binding construct targeting HER2 comprises a first polypeptide chain having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 17, a second polypeptide chain having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 18, and a third polypeptide chain having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 19. In some embodiments, the antigen binding construct targeting HER2 comprises a first polypeptide chain having the amino acid sequence set forth in SEQ ID NO: 17, a second polypeptide chain having the amino acid sequence set forth in SEQ ID NO: 18, and a third polypeptide chain having the amino acid sequence set forth in SEQ ID NO: 19.In some embodiments, the antigen binding construct targeting HER2 comprises a first polypeptide chain comprising a HCDR1 having the amino acid sequence set forth in SEQ ID NO: 1, a HCDR2 having the amino acid sequence set forth in SEQ ID NO: 2, and a HCDR3 having the amino acid sequence set forth in SEQ ID NO: 3, a second polypeptide chain comprising a LCDR1 having the amino acid sequence set forth in SEQ ID NO: 4, a LCDR2 having the amino acid sequence set forth in SEQ ID NO: 5, and a LCDR3 having the amino acid sequence set forth in SEQ ID NO: 6, and a third polypeptide chain comprising a LCDR1 having the amino acid sequence set forth in SEQ ID NO: 12, a LCDR2 having the amino acid sequence set forth in SEQ ID NO: 13, and a LCDR3 having the amino acid sequence set forth in SEQ ID NO: 14, and the first polypeptide chain comprises an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 17, the second polypeptide chain comprises an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 18, and the third polypeptide chain comprises an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 19.

[0057] In some embodiments, the antigen binding construct targeting HER2 comprises a first polypeptide chain comprising a HCDR1 having the amino acid sequence set forth in SEQ ID NO: 1, a HCDR2 having the amino acid sequence set forth in SEQ ID NO: 2, and a HCDR3 having the amino acid sequence set forth in SEQ ID NO: 3, a second polypeptide chain comprising a LCDR1 having the amino acid sequence set forth in SEQ ID NO: 4, a LCDR2 having the amino acid sequence set forth in SEQ ID NO: 5, and a LCDR3 having the amino acid sequence set forth in SEQ ID NO: 6, and a third polypeptide chain comprising a LCDR1 having the amino acid sequence set forth in SEQ ID NO: 12, a LCDR2 having the amino acid sequence set forth in SEQ ID NO: 13, and a LCDR3 having the amino acid sequence set forth in SEQ ID NO: 14, and the first polypeptide chain comprises an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 17, the second polypeptide chain comprises an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 18, and the third polypeptide chain comprises an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 19.

[0058] In some embodiments, the difference amino acid in the amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 17, 18, or 19 is located in the FR region or the constant region, compared to the amino acid sequence set forth in SEQ ID NO: 17, 18, or 19.

[0059] In some embodiments, the C-terminal lysine of the amino acid sequence set forth in SEQ ID NO: 17 is deleted, as set forth in SEQ ID NO: 20. In some embodiments, the C-terminal lysine of the amino acid sequence set forth in SEQ ID NO: 18 is deleted, as set forth in SEQ ID NO: 21. In some embodiments, the C-terminal lysine of the first polypeptide chain and the second polypeptide chain is deleted, the amino acid sequence of the first polypeptide chain is set forth in SEQ ID NO: 20, and the amino acid sequence of the second polypeptide chain is set forth in SEQ ID NO: 21.

[0060] In other embodiments, the antigen binding construct targeting HER2 is selected from Expi Her2-1, Expi Her2-3, Expi Her2-4, Expi Her2-5, 23C2 Her2-1, 23C2 Her2-3, 23C2 Her2-4, or 23C2 Her2-5 (see WO2021219046 or CN115279791A). In other embodiments, the antigen binding construct targeting HER2 is selected from Zanidatamab (ZW25), KN026, MBS301, KM257, or BCD-147.

[0061] The anti-HER2 antibody drug conjugate used in the present disclosure can also be represented by the structure shown in Formula II:

[0062] wherein the antigen binding construct targeting HER2 is as described above. In some embodiments, the drug-linker is connected to the antigen binding construct targeting HER2 through a thioether bond. n has the same meaning as DAR, representing the average number of cytotoxic drugs connected to each antigen binding construct targeting HER2. In some embodiments, n is 2 to 8. In some embodiments, n is 4 to 7. In some embodiments, n is 5 to 6. In some embodiments, n is 5.5 to 6. In some embodiments, n is 5.8 to 6.

[0063] The antibody drug conjugate preferably used in the present disclosure is formed by linking a drug-linker of the structure shown in formula Ia below to a HER2-targeting antigen binding construct,

[0064] wherein,

[0065] the 3-position of -(succinimid-3-yl-N)- in formula Ia is linked to the HER2-targeting antigen binding construct,

[0066] the HER2-targeting antigen binding construct is composed of three polypeptide chains, the amino acid sequence of the first polypeptide chain is shown in SEQ ID NO: 17 or a C-terminal lysine deletion variant thereof, the amino acid sequence of the second polypeptide chain is shown in SEQ ID NO: 18 or a C-terminal lysine deletion variant thereof, and the amino acid sequence of the third polypeptide chain is shown in SEQ ID NO: 19 (for example, the amino acid sequence of the first polypeptide chain is shown in SEQ ID NO: 17, the amino acid sequence of the second polypeptide chain is shown in SEQ ID NO: 18, and the amino acid sequence of the third polypeptide chain is shown in SEQ ID NO: 19; or the amino acid sequence of the first polypeptide chain is shown in SEQ ID NO: 20, the amino acid sequence of the second polypeptide chain is shown in SEQ ID NO: 21, and the amino acid sequence of the third polypeptide chain is shown in SEQ ID NO: 19; or the amino acid sequence of the first polypeptide chain is shown in SEQ ID NO: 20, the amino acid sequence of the second polypeptide chain is shown in SEQ ID NO: 18, and the amino acid sequence of the third polypeptide chain is shown in SEQ ID NO: 19; or the amino acid sequence of the first polypeptide chain is shown in SEQ ID NO: 17, the amino acid sequence of the second polypeptide chain is shown in SEQ ID NO: 21, and the amino acid sequence of the third polypeptide chain is shown in SEQ ID NO: 19), and

[0067] For 1 HER2-targeting antigen binding construct, the average number of drug-linker linkages is 5 to 6.

[0068] In some embodiments, the 3-position of -(succinimid-3-yl-N)- in formula Ia is linked to the HER2-targeting antigen binding construct via a thioether bond.

[0069] The antibody drug conjugate preferably used in the present disclosure can also be represented by the structure shown in formula II below:

[0070] wherein n is 5 to 6,

[0071] The antigen binding construct targeting HER2 consists of three polypeptide chains, the amino acid sequence of the first polypeptide chain is set forth in SEQ ID NO: 17 or a C-terminal lysine-deleted variant thereof, the amino acid sequence of the second polypeptide chain is set forth in SEQ ID NO: 18 or a C-terminal lysine-deleted variant thereof, and the amino acid sequence of the third polypeptide chain is set forth in SEQ ID NO: 19 (e.g., the amino acid sequence of the first polypeptide chain is set forth in SEQ ID NO: 17, the amino acid sequence of the second polypeptide chain is set forth in SEQ ID NO: 18, and the amino acid sequence of the third polypeptide chain is set forth in SEQ ID NO: 19; or, the amino acid sequence of the first polypeptide chain is set forth in SEQ ID NO: 20, the amino acid sequence of the second polypeptide chain is set forth in SEQ ID NO: 21, and the amino acid sequence of the third polypeptide chain is set forth in SEQ ID NO: 19; or, the amino acid sequence of the first polypeptide chain is set forth in SEQ ID NO: 20, the amino acid sequence of the second polypeptide chain is set forth in SEQ ID NO: 18, and the amino acid sequence of the third polypeptide chain is set forth in SEQ ID NO: 19; or, the amino acid sequence of the first polypeptide chain is set forth in SEQ ID NO: 17, the amino acid sequence of the second polypeptide chain is set forth in SEQ ID NO: 21, and the amino acid sequence of the third polypeptide chain is set forth in SEQ ID NO: 19). In some embodiments, the drug-linker is linked to the antigen binding construct targeting HER2 through a thioether bond.

[0072] In some specific embodiments, the anti-HER2 antibody drug conjugate of the present disclosure is selected from MRG002, ARX788, A166, SHR-A1811, BB-1701, SYD985, FS-1502, or BAT8001.

[0073] The anti-HER2 antibody drug conjugate described in the present disclosure also includes an isomer, a pharmaceutically acceptable salt of the anti-HER2 antibody drug conjugate, or a solvate of the anti-HER2 antibody drug conjugate, an isomer thereof, a pharmaceutically acceptable salt thereof.

[0074] Technical effects

[0075] The administration of the anti-HER2 antibody drug conjugate of the present disclosure has one or several of the following effects:

[0076] (1) produces a benefit to a biliary tract cancer subject, preferably unresectable locally advanced and / or metastatic biliary tract cancer, including but not limited to intrahepatic cholangiocarcinoma, perihilar cholangiocarcinoma, distal cholangiocarcinoma, or gallbladder cancer;

[0077] (2) has good safety;

[0078] (3) is well tolerated in the subject.

[0079] Definitions and Descriptions

[0080] The following terms used in the present disclosure have the following meanings unless otherwise indicated. A particular term should not be construed as indefinite or unclear if not specifically defined, but should be understood in accordance with the ordinary meaning in the art. When a trade name appears in the present disclosure, it is intended to refer to its corresponding product or active ingredient thereof.

[0081] As used herein, the structure of “-(succinimid-3-yl-N)-” is as follows:

[0082] Unless otherwise indicated, a solid wedge-shaped bond and a dashed wedge-shaped bond indicate the absolute configuration of a stereocenter.

[0083] Unless otherwise specified, when a group has available sites of attachment, the attachment of that group to other groups can be indicated by a wavy line .

[0084] The term “antigen binding construct” refers to any agent, such as a polypeptide or polypeptide complex, that is capable of binding to an antigen. In some aspects, an antigen binding construct is a polypeptide that specifically binds to a target antigen. An antigen binding construct can be a monomer, a dimer, a multimer, a protein, a peptide, a protein or peptide complex, an antibody or antigen binding fragment thereof, etc. An antigen binding construct can be a monospecific, bispecific, or multispecific polypeptide construct. In some aspects, an antigen binding construct can include, for example, one or more antigen binding fragments (e.g., Fab or scFv) linked to one or more Fc.

[0085] An "antigen-binding fragment" of an antibody refers to one or more fragments of an antibody that retain the ability to specifically bind to an antigen (e.g., a HER2 protein). It has been shown that the antigen binding function of an antibody can be performed by fragments of a full-length antibody. Examples of fragments encompassed within the term "antigen-binding fragment" of an antibody include (i) a Fab fragment, a monovalent fragment consisting of the VL, VH, CL, and CHI domains; (ii) a F(ab')2 fragment, a bivalent fragment comprising two Fab fragments linked by a disulfide bridge at the hinge region; (iii) a Fd fragment consisting of the VH and CHI domains; (iv) a Fv fragment consisting of the VL and VH domains of a single arm of an antibody; (v) a dAb fragment (see, e.g., Ward et al., Nature. 341 :544-546 (1989)), which consists of a VH domain; and (vi) a Nanobody, a small antibody consisting of a single variable domain and two constant domains. Furthermore, although the two domains of the Fv fragment, VL and VH, are coded for by separate genes, they can be joined, using recombinant methods, by a linker that enables them to be made as a single protein chain in which the VL and VH regions pair to form monovalent molecules known as single chain Fv (scFv) (see, e.g., Bird et al., Science. 242:423-426 (1988); Huston et al., Proc. Natl. Acad. Sci. 85:5879-5883 (1988)), these single chain antibodies are also encompassed within the term antigen-binding fragment. These antibody fragments are obtained using conventional techniques known to those with ordinary skill in the art, and the fragments are screened for utility in the same manner as are full-length antibodies.

[0086] The term "identity" also is referred to as identity. The "percentage (%) of identity" of an amino acid sequence refers to the percentage of amino acid residues in the sequence to be aligned which are identical with the amino acid residues of the specific amino acid sequence set forth herein, after aligning the sequences to be compared and introducing gaps, if necessary, to achieve the maximum % sequence identity, and not considering any conservative changes as part of the sequence identity. Amino acid sequence alignment for purposes of determining % identity can be achieved using any of a number of well-known methods, for example, BLAST, BLAST-2, ALIGN, or Megalign (DNASTAR) software. Those skilled in the art can determine appropriate parameters for aligning sequences, including any algorithms needed to achieve the maximum alignment over the full length of the sequences being compared.

[0087] The term "treatment" means the administration of a compound of the present disclosure to prevent, ameliorate or eliminate a disease or one or more symptoms associated with the disease, and includes, but is not limited to:

[0088] (i) preventing the disease or condition from occurring in a mammal, in particular, when such mammal is predisposed to the disease but has not yet been diagnosed as having it;

[0089] (ii) inhibiting the disease or condition, i.e., arresting its development;

[0090] (iii) relieving the disease or condition, i.e., causing regression of the disease or condition;

[0091] (iv) reducing any direct or indirect pathological consequence of the disease or condition.

[0092] The term "therapeutically effective amount" means an amount of a compound of the present disclosure that (i) treats or prevents the particular disease, condition, or disorder, (ii) attenuates, ameliorates, or eliminates one or more symptoms of the particular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of the particular disease, condition, or disorder described herein. The amount of a compound of the present disclosure that will constitute a "therapeutically effective amount" will vary depending on, inter alia, the compound and its ability to elicit a desired response in the individual, the disorder and its severity, the manner of administration, and the age, sex, and weight of the mammal to be treated.

[0093] The term "administering" or "administered" means physically introducing a therapeutic agent into a subject using any of a variety of methods and delivery systems known to those skilled in the art.

[0094] Routes of administration of antibody drug conjugates (e.g., anti-HER2 antibody drug conjugates) include intravenous, intramuscular, intraperitoneal, spinal or other parenteral routes of administration. The term "parenteral administration" as used herein refers to modes of administration other than enteral, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intralymphatic, intralesional, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcutaneous, intraarticular, subcapsular, subarachnoid, intraspinal, epidural and intrasternal injection and infusion, as well as in vivo electroporation. Administration can also be performed, e.g., once, multiple times, and / or over one or more extended periods of time.

[0095] The term "pharmaceutically acceptable" in reference to compounds, materials, compositions, and / or dosage forms is employed herein to describe a carrier, diluent, or vehicle that is compatible with the other ingredients of a pharmaceutical composition and not deleterious to the recipient thereof.

[0096] The term "pharmaceutically acceptable salt" refers to a salt of a compound (e.g., an antibody drug conjugate of the present disclosure) that is safe and effective for use in a mammal, and that possesses the desired biological activity, e.g., can be a metal salt, an ammonium salt, a salt of an organic base, a salt of an inorganic acid, a salt of an organic acid, a salt of a basic or acidic amino acid, and the like.

[0097] The term "excipient" refers to any ingredient other than the active ingredient (e.g., an antibody drug conjugate of the present disclosure). The choice of excipient will to a large extent depend on factors such as the particular mode of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form.

[0098] The term "solvate" refers to a compound associated with a solvent molecule.

[0099] The term "HER2-positive" in the present disclosure is not particularly limited as long as it is recognized by those skilled in the art as a HER2-positive cholangiocarcinoma, and preferably refers to, for example, a cholangiocarcinoma in which the expression of HER2 is determined to be 3+ (i.e., IHC 3+) by immunohistochemistry (IHC), or / and a cholangiocarcinoma in which the expression of HER2 is determined to be 2+ by IHC and the expression of HER2 is determined to be positive (i.e., IHC 2+ and ISH+) by in situ hybridization (ISH). It should be noted that the in situ hybridization method of the present disclosure includes, but is not limited to, fluorescence in situ hybridization (FISH) or dual-color in situ hybridization (DISH).

[0100] The terms "subject," "patient," or "host" are used interchangeably herein and include any animal, including mammals, e.g., humans. The term "non-human animal" includes, but is not limited to, vertebrates such as non-human primates, sheep, dogs, and rodents such as mice, rats, and hamsters. In some embodiments, the subject, patient, or host is a mammal. In some embodiments, the subject, patient, or host is a mouse. In some embodiments, the subject, patient, or host is a human.

[0101] The term "pharmaceutical composition" refers to a mixture of one or more active ingredients (e.g., an anti-HER2 antibody drug conjugate of the present disclosure) with a pharmaceutically acceptable excipient. The purpose of a pharmaceutical composition is to facilitate administration of the active ingredients to a subject. The terms "pharmaceutical composition" and "formulation" have the same meaning and are used interchangeably herein.

[0102] The words "comprise," "comprises," or "comprising" and variations thereof, such as "comprises" or "comprising," are to be interpreted generically and do not exclude other steps.

[0103] In this document, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise.

[0104] As used herein, "about" means an acceptable range of error for the particular value specified, as determined by one of ordinary skill in the art to which the value pertains, which is recognized to vary somewhat from the nominal specified value. For example, "about" can mean within 1 or more than 1 standard deviation per the practice in the art. Alternatively, "about" can mean ranges up to ± 5% of a given value, such as within ± 2% of a given range, ± 1% of a given range, or ± 0.5% of a given range. When a particular value is given in the disclosure or claims, the meaning of "about" should be considered to be within an acceptable range of error for that particular value unless otherwise noted. In this document, all dosages, times, step parameters, or conditions for dosage, unless otherwise indicated, are by default modified by "about."

[0105] All patents, patent applications, and other publications identified are expressly incorporated herein by reference for the purposes of describing and disclosing, for example, the methodologies described therein and methodologies which could be used in the practice of the present disclosure. The publications discussed herein are provided solely for their disclosure prior to the filing date of the present application. Nothing herein is to be construed as an admission that the publications, including publications made by the applicant and / or the same inventors of the present disclosure, are prior art. Moreover, the citation of any reference is not an admission that it is prior art with respect to a presently claimed disclosure, and likewise, the citation of any prior art does not constitute an admission that the present disclosure is not entitled to antedate such citation. Further, the references cited herein are not admitted to be prior art to the claimed disclosure, and are included only to further describe the state of the art. In addition, any priority document referenced herein is incorporated by reference herein.

[0106] The present disclosure also provides the following specific embodiments, but the scope of protection of the present disclosure is not limited thereto:

[0107] Embodiment 1. A method of treating biliary tract cancer in a subject, comprising administering to the subject an anti-HER2 antibody drug conjugate, wherein the anti-HER2 antibody drug conjugate is of the following formula la

[0108] the drug-linker of the structure shown is attached to an antigen binding construct targeting HER2,

[0109] the 3-position of -(succinimid-3-yl-N)- in formula la is attached to an antigen binding construct targeting HER2,

[0110] The antigen binding construct targeting HER2 comprises a first antigen binding fragment comprising a HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 1, a HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 2, a HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 3, a LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 4, a LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 5, and a LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 6, and a second antigen binding fragment comprising a HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 9, a HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 10, a HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 11, a LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 13, and a LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 14.

[0111] Embodiment 2. The method of embodiment 1, wherein the average number of drug-linker attachments per each antigen binding construct targeting HER2 is from 4 to 7.

[0112] Embodiment 3. The method of embodiment 2, wherein the average number of drug-linker attachments per each antigen binding construct targeting HER2 is from 5 to 6.

[0113] Embodiment 4. The method of embodiment 3, wherein the average number of drug-linker attachments per each antigen binding construct targeting HER2 is from 5.5 to 6.

[0114] Embodiment 5. The method of any one of embodiments 1-4, wherein,

[0115] (i) the first antigen binding fragment comprises a heavy chain variable region having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 7;

[0116] (ii) the first antigen binding fragment comprises a light chain variable region having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 8;

[0117] (iii) the first antigen binding fragment comprises a heavy chain variable region having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 7, and a light chain variable region having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 8;

[0118] (iv) the second antigen binding fragment comprises a heavy chain variable region having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 15;

[0119] (v) the second antigen binding fragment comprises a light chain variable region having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 16;

[0120] (vi) the second antigen binding fragment comprises a heavy chain variable region having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 15, and a light chain variable region having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 16; or

[0121] (vii) the first antigen binding fragment comprises a heavy chain variable region having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 7, and a light chain variable region having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 8; and, the second antigen binding fragment comprises a heavy chain variable region having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 15, and a light chain variable region having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 16.

[0122] Embodiment 6. The method of any one of embodiments 1-5, wherein,

[0123] (i) the HER2-targeting antigen binding construct comprises a first polypeptide chain having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 17 or 20;

[0124] (ii) the HER2-targeting antigen binding construct comprises a second polypeptide chain having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 18 or 21;

[0125] (iii) the HER2-targeting antigen binding construct comprises a third polypeptide chain having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 19;

[0126] (iv) the HER2-targeting antigen binding construct comprises a first polypeptide chain having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 17 or 20, a second polypeptide chain having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 18 or 21, and a third polypeptide chain having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 19;

[0127] (v) the HER2-targeting antigen binding construct comprises a first polypeptide chain having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 17, a second polypeptide chain having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 18, and a third polypeptide chain having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 19;

[0128] (vi) the HER2-targeting antigen binding construct comprises a first polypeptide chain having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 20, a second polypeptide chain having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 21, and a third polypeptide chain having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 19;

[0129] (vii) the HER2-targeting antigen binding construct comprises a first polypeptide chain having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 17, a second polypeptide chain having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 21, and a third polypeptide chain having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 19; or

[0130] (viii) the HER2-targeting antigen binding construct comprises a first polypeptide chain having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 20, a second polypeptide chain having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 18, and a third polypeptide chain having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 19.

[0131] Embodiment 7. The method of any one of embodiments 1-6, wherein the anti-HER2 antibody drug conjugate is administered in a therapeutically effective amount.

[0132] Embodiment 8. The method of any one of embodiments 1-7, wherein the anti-HER2 antibody drug conjugate is administered at a dose of 1.5-9 mg / kg, 4.5-7.5 mg / kg, 4.5-6 mg / kg, 5.4-7.5 mg / kg, or 6-7.5 mg / kg per dose; preferably, the anti-HER2 antibody drug conjugate is administered at a dose of 6-7.5 mg / kg per dose.

[0133] Embodiment 9. The method of embodiment 8, wherein the anti-HER2 antibody drug conjugate is administered at a dose of 1.5 mg / kg, 3 mg / kg, 4.5 mg / kg, 5.4 mg / kg, 6 mg / kg, 7.5 mg / kg, or 9 mg / kg per dose; preferably, the anti-HER2 antibody drug conjugate is administered at a dose of 6 mg / kg or 7.5 mg / kg per dose.

[0134] Embodiment 10. The method of any one of embodiments 1-9, wherein the anti-HER2 antibody drug conjugate is administered once every 1 week, once every 2 weeks, once every 3 weeks, or once every 4 weeks; preferably, the anti-HER2 antibody drug conjugate is administered once every 3 weeks.

[0135] Embodiment 11. The method of any one of embodiments 1-10, wherein the anti-HER2 antibody drug conjugate is formulated as a preparation for intravenous injection or infusion.

[0136] Embodiment 12. The method of any one of embodiments 1-11, wherein the administration of the anti-HER2 antibody drug conjugate is by intravenous infusion.

[0137] Embodiment 13. The method of any one of embodiments 1-12, wherein the biliary tract cancer is locally advanced biliary tract cancer.

[0138] Embodiment 14. The method of any one of embodiments 1-12, wherein the biliary tract cancer is recurrent biliary tract cancer.

[0139] Embodiment 15. The method of any one of embodiments 1-12, wherein the biliary tract cancer is metastatic biliary tract cancer.

[0140] Embodiment 16. The method of any one of embodiments 1-15, wherein the biliary tract cancer is unresectable biliary tract cancer.

[0141] Embodiment 17. The method of any one of embodiments 1-16, wherein the biliary tract cancer is unresectable locally advanced and / or metastatic biliary tract cancer.

[0142] Embodiment 18. The method of any one of embodiments 1-17, wherein the biliary tract cancer is a HER2-expressing, -amplified, or -mutated biliary tract cancer.

[0143] Embodiment 19. The method of any one of embodiments 1-18, wherein the biliary tract cancer is a HER2-positive biliary tract cancer.

[0144] Embodiment 20. The method of embodiment 19, wherein the HER2-positive biliary tract cancer is a biliary tract cancer in which the expression of HER2 is determined to be 3+ by IHC.

[0145] Embodiment 21. The method of embodiment 19, wherein the HER2-positive biliary tract cancer is a biliary tract cancer in which the expression of HER2 is determined to be 2+ by IHC and positive by ISH.

[0146] Embodiment 22. The method of any one of embodiments 1-21, wherein the subject with the biliary tract cancer has previously received at least one line of therapy to treat the biliary tract cancer.

[0147] Embodiment 23. The method of embodiment 22, wherein the subject with the biliary tract cancer has previously received at least one line of chemotherapy to treat the biliary tract cancer.

[0148] Embodiment 24. The method of any one of embodiments 1-23, wherein the subject with the biliary tract cancer has previously received gemcitabine, a platinum drug, and / or a fluorouracil drug to treat the biliary tract cancer.

[0149] Embodiment 25. The method of any one of embodiments 1-24, wherein the subject is a subject with HER2-positive locally advanced or metastatic biliary tract cancer who has failed at least one line of chemotherapy.

[0150] Embodiment 26. The method of any one of embodiments 1-25, wherein the anti-HER2 antibody drug conjugate is used to treat the biliary tract cancer in the subject in the second line of therapy or more.

[0151] Embodiment 27. The method of any one of embodiments 1-26, wherein the biliary tract cancer is cholangiocarcinoma or gallbladder cancer.

[0152] Embodiment 28. The method of any one of embodiments 1-27, wherein the biliary tract cancer is intrahepatic cholangiocarcinoma, perihilar cholangiocarcinoma, or distal cholangiocarcinoma.

[0153] Embodiment 29. Use of an anti-HER2 antibody drug conjugate in the manufacture of a medicament for treating a biliary tract cancer in a subject, wherein the anti-HER2 antibody drug conjugate is of the following formula Ia

[0154] the drug-linker of the structure shown is linked to a HER2-targeting antigen binding construct,

[0155] position 3 of -(succinimid-3-yl-N)- in Formula la is linked to a HER2-targeting antigen binding construct,

[0156] the HER2-targeting antigen binding construct comprises a first antigen binding fragment comprising a HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 1, a HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 2, a HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 3, a LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 4, a LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 5, and a LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 6, and a second antigen binding fragment comprising a HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 9, a HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 10, a HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 11, a LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 13, and a LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 14.

[0157] Embodiment 30. The use according to embodiment 29, wherein the average number of linkages of the drug-linker per HER2-targeting antigen binding construct is from 4 to 7.

[0158] Embodiment 31. The use according to embodiment 30, wherein the average number of linkages of the drug-linker per HER2-targeting antigen binding construct is from 5 to 6.

[0159] Embodiment 32. The use according to embodiment 31, wherein the average number of linkages of the drug-linker per HER2-targeting antigen binding construct is from 5.5 to 6.

[0160] Embodiment 33. The use according to any one of embodiments 29-32, wherein,

[0161] (i) the first antigen binding fragment comprises a heavy chain variable region having an amino acid sequence which is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 7;

[0162] (ii) the first antigen binding fragment comprises a light chain variable region having an amino acid sequence which is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 8;

[0163] (iii) the first antigen binding fragment comprises a heavy chain variable region having an amino acid sequence which is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 7, and a light chain variable region having an amino acid sequence which is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 8;

[0164] (iv) the second antigen binding fragment comprises a heavy chain variable region having an amino acid sequence which is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 15;

[0165] (v) the second antigen binding fragment comprises a light chain variable region having an amino acid sequence which is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 16;

[0166] (vi) the second antigen binding fragment comprises a heavy chain variable region having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 15, and a light chain variable region having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 16; or

[0167] (vii) the first antigen binding fragment comprises a heavy chain variable region having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 7, and a light chain variable region having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 8; and, the second antigen binding fragment comprises a heavy chain variable region having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 15, and a light chain variable region having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 16.

[0168] Embodiment 34. The use according to any one of embodiments 29-33, wherein,

[0169] (i) the HER2-targeting antigen binding construct comprises a first polypeptide chain having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 17 or 20;

[0170] (ii) the HER2-targeting antigen binding construct comprises a second polypeptide chain having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 18 or 21;

[0171] (iii) the HER2-targeting antigen binding construct comprises a third polypeptide chain having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 19;

[0172] (iv) the HER2-targeting antigen binding construct comprises a first polypeptide chain having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 17 or 20, a second polypeptide chain having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 18 or 21, and a third polypeptide chain having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 19;

[0173] (v) the HER2-targeting antigen binding construct comprises a first polypeptide chain having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 17, a second polypeptide chain having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 18, and a third polypeptide chain having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 19;

[0174] (vi) the HER2-targeting antigen binding construct comprises a first polypeptide chain having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 20, a second polypeptide chain having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 21, and a third polypeptide chain having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 19;

[0175] (vii) the antigen binding construct targeting HER2 comprises a first polypeptide chain having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 17, a second polypeptide chain having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 21, and a third polypeptide chain having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 19; or

[0176] (viii) the antigen binding construct targeting HER2 comprises a first polypeptide chain having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 20, a second polypeptide chain having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 18, and a third polypeptide chain having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 19.

[0177] Embodiment 35. The use according to any one of embodiments 29-34, wherein the medicament comprises a therapeutically effective amount of the anti-HER2 antibody drug conjugate.

[0178] Embodiment 36. The use of any one of embodiments 29-35, wherein the anti-HER2 antibody drug conjugate is administered at a dose of 1.5-9 mg / kg, 4.5-7.5 mg / kg, 4.5-6 mg / kg, 5.4-7.5 mg / kg, or 6-7.5 mg / kg per dose; preferably, the anti-HER2 antibody drug conjugate is administered at a dose of 6-7.5 mg / kg per dose.

[0179] Embodiment 37. The use of embodiment 36, wherein the anti-HER2 antibody drug conjugate is administered at a dose of 1.5 mg / kg, 3 mg / kg, 4.5 mg / kg, 5.4 mg / kg, 6 mg / kg, 7.5 mg / kg, or 9 mg / kg per dose; preferably, the anti-HER2 antibody drug conjugate is administered at a dose of 6 mg / kg or 7.5 mg / kg per dose.

[0180] Embodiment 38. The use of any one of embodiments 29-37, wherein the anti-HER2 antibody drug conjugate is administered once every 1 week, once every 2 weeks, once every 3 weeks, or once every 4 weeks; preferably, the anti-HER2 antibody drug conjugate is administered once every 3 weeks.

[0181] Embodiment 39. The use of any one of embodiments 29-38, wherein the anti-HER2 antibody drug conjugate is formulated as a formulation for intravenous injection or infusion.

[0182] Embodiment 40. The use of any one of embodiments 29-39, wherein the administration of the anti-HER2 antibody drug conjugate is performed as an intravenous infusion.

[0183] Embodiment 41. The use of any one of embodiments 29-40, wherein the biliary tract cancer is locally advanced biliary tract cancer.

[0184] Embodiment 42. The use of any one of embodiments 29-40, wherein the biliary tract cancer is recurrent biliary tract cancer.

[0185] Embodiment 43. The use of any one of embodiments 29-40, wherein the biliary tract cancer is metastatic biliary tract cancer.

[0186] Embodiment 44. The use of any one of embodiments 29-43, wherein the biliary tract cancer is unresectable biliary tract cancer.

[0187] Embodiment 45. The use of any one of embodiments 29-44, wherein the biliary tract cancer is unresectable locally advanced and / or metastatic biliary tract cancer.

[0188] Embodiment 46. The use of any one of embodiments 29-45, wherein the biliary tract cancer is a HER2 expressing, amplifying, or mutant biliary tract cancer.

[0189] Embodiment 47. The use of any one of embodiments 29-46, wherein the biliary tract cancer is a HER2 positive biliary tract cancer.

[0190] Embodiment 48. The use of embodiment 47, wherein the HER2 positive biliary tract cancer is a biliary tract cancer in which the expression of HER2 is determined to be 3+ by IHC.

[0191] Embodiment 49. The use of embodiment 47, wherein the HER2 positive biliary tract cancer is a biliary tract cancer in which the expression of HER2 is determined to be 2+ by IHC and the expression of HER2 is determined to be positive by ISH.

[0192] Embodiment 50. The use of any one of embodiments 29-49, wherein the subject with biliary tract cancer has previously received at least one line of therapy to treat the biliary tract cancer.

[0193] Embodiment 51. The use of embodiment 50, wherein the subject with biliary tract cancer has previously received at least one line of chemotherapy to treat the biliary tract cancer.

[0194] Embodiment 52. The use of any one of embodiments 29-51, wherein the subject with biliary tract cancer has previously received gemcitabine, a platinum drug, and / or a fluorouracil drug to treat the biliary tract cancer.

[0195] Embodiment 53. The use of any one of embodiments 29-52, wherein the subject is a subject with HER2 positive locally advanced or metastatic biliary tract cancer who has failed at least one line of chemotherapy.

[0196] Embodiment 54. The use of any one of embodiments 29-53, wherein the anti-HER2 antibody drug conjugate is used to treat the biliary tract cancer in the subject in the second line of therapy or more.

[0197] Embodiment 55. The use of any one of embodiments 29-54, wherein the biliary tract cancer is cholangiocarcinoma or gallbladder cancer.

[0198] Embodiment 56. The use of any one of embodiments 29-55, wherein the biliary tract cancer is intrahepatic cholangiocarcinoma, perihilar cholangiocarcinoma, or distal cholangiocarcinoma. EXAMPLE

[0199] For the sake of clarity, the present disclosure is further defined by the following examples, but the scope of the disclosure is not limited by the examples.

[0200] The entire contents of the patent application files of WO2022033578 or CN115702008A are incorporated into the present disclosure. The anti-HER2 antibody drug conjugate in the following examples is an anti-HER2 antibody drug conjugate represented by the following formula (hereinafter referred to as ADC1) prepared according to the preparation method described in WO2022033578:

[0201] wherein the drug-linker is connected to the HER2-targeting antigen binding construct through a thioether bond, n is 5 to 6, and in brief, the nucleic acid sequences encoding the three polypeptide chains (the amino acid sequences are shown in SEQ ID NOs: 17, 18 and 19, respectively) of the HER2-targeting antigen binding construct are cloned into pcDNA3.1 expression vectors, respectively, co-transfected into FUT8-knocked-out CHO-S cells for expression, and purified by protein A to prepare the HER2-targeting antigen binding construct. The HER2-targeting antigen binding construct is treated with tris(2-carboxyethyl)phosphine hydrochloride, and then reacted with a linker-payload selected from the structures represented by the following formula to finally obtain ADC1:

[0202] Example 1: Ib / II phase clinical trial of HER2-expressing biliary tract cancer

[0203] 1. Objectives of the study:

[0204] 1.1 Ib phase

[0205] 1.1.1 Primary objective:

[0206] To evaluate the safety of ADC1 in the treatment of HER2-positive locally advanced or metastatic biliary tract cancer;

[0207] To determine the recommended phase II dose (RP2D);

[0208] 1.1.2 Secondary objectives:

[0209] To evaluate the efficacy of ADC1 in the treatment of HER2-positive locally advanced or metastatic biliary tract cancer.

[0210] 1.2 II phase

[0211] 1.2.1 Primary objective:

[0212] To evaluate the efficacy of ADC1 in the treatment of HER2-positive locally advanced or metastatic biliary tract cancer;

[0213] 1.2.2 Secondary objectives:

[0214] To evaluate the safety of ADC1 in the treatment of HER2-positive locally advanced or metastatic biliary tract cancer.

[0215] 2. Inclusion Criteria

[0216] Subjects who meet all of the following inclusion criteria are eligible for enrollment in this trial:

[0217] (1) Age: 18 to 75 years (calculated from the date of signing informed consent form);

[0218] (2) ECOG performance status: 0 to 1 score;

[0219] (3) Life expectancy of greater than 12 weeks;

[0220] (4) Subjects with HER2 expression or amplification or mutation detected, require immunohistochemistry HER2 3+, or HER2 2+ and ISH positive;

[0221] (5) Adequate major organ function, with normal laboratory values for hematology, blood chemistry, urinalysis, and coagulation function;

[0222] (6) Meets the criteria for advanced biliary tract cancer:

[0223] 1) Histologically or cytologically confirmed biliary tract cancer, including intrahepatic cholangiocarcinoma (iCCA), perihilar cholangiocarcinoma (pCCA), distal cholangiocarcinoma (dCCA), and gallbladder cancer (GBC);

[0224] 2) Locally advanced, recurrent, and / or metastatic disease that is not amenable to surgical resection, with at least 1 measurable lesion according to RECIST 1.1 criteria;

[0225] 3) Patients who have failed at least one prior chemotherapy; failure of first-line chemotherapy is defined as disease progression (with evidence of disease progression on imaging) during or within 3 months after treatment with a single-agent or combination chemotherapy regimen based on gemcitabine, platinum, or fluorouracil, or intolerance to drug toxicity, or disease progression or recurrence within 6 months after neoadjuvant / adjuvant therapy;

[0226] (7) Women of childbearing potential must agree to use effective contraception from the time of signing the informed consent form until 6 months after the end of the study, and have a negative serum or urine pregnancy test within 7 days before study entry; men must agree to use effective contraception from the time of signing the informed consent form until 6 months after the end of the study;

[0227] (8) Subjects voluntarily join this study, sign the informed consent form, and have good compliance.

[0228] 3. Trial Drug

[0229] ADC1 for injection (specification: 100 mg / bottle) is developed and provided by Nanjing Shunxin Pharmaceutical Co., Ltd., of Sinotrust Pharmaceutical Group.

[0230] 4. Treatment regimen

[0231] Intravenous infusion, dose of 6 mg / kg or 7.5 mg / kg, every 3 weeks (21 days) for 1 treatment cycle, 1 administration of ADC1 per treatment cycle (dose window period of ± 3 days from the planned administration time), until disease progression, intolerance, subject's active request to terminate study treatment, or the investigator's decision that the subject needs to be withdrawn from the study.

[0232] Adjustments can be made according to the severity of the disease, the response of the disease, any treatment-related toxicity, the age and health status of the patient.

[0233] 5. Evaluation criteria

[0234] Evaluation of effectiveness: the RECIST 1.1 standard is used to determine the disease status.

[0235] Safety evaluation: the NCI-CTC AE 5.0 standard is used to determine the severity of adverse events.

[0236] 6. Endpoint indicators

[0237] 6.1 Phase I

[0238] a) Primary endpoint:

[0239] The incidence and severity of adverse events (AEs) and serious adverse events (SAEs), as well as abnormal laboratory test indicators;

[0240] Phase II recommended dose (RP2D);

[0241] b) Secondary endpoints:

[0242] Objective response rate (ORR) assessed by the investigator, progression-free survival (PFS), disease control rate (DCR), disease remission time (DOR); overall survival (OS);

[0243] The incidence and severity of AEs and SAEs, as well as abnormal laboratory test indicators.

[0244] 6.2 Phase II

[0245] a) Primary endpoint:

[0246] ORR assessed by the independent review committee (IRC)

[0247] b) Secondary endpoints:

[0248] ORR assessed by the investigator;

[0249] DCR, PFS, DOR, time to disease progression (TTP), time to remission (TTR) assessed by the investigator and the IRC;

[0250] OS;

[0251] Incidence and severity of AE and SAE, and abnormal laboratory test indicators.

[0252] 7. Results

[0253] By the clinical data collection date, a total of 27 patients with biliary tract cancer (including patients with intrahepatic cholangiocarcinoma, hilar cholangiocarcinoma, distal cholangiocarcinoma and gallbladder cancer) in the 7.5 mg / kg dose group reached an evaluable degree, of which 15 patients reached PR (partial remission), 11 patients reached SD (stable disease; 10 of which were SD-), 1 patient had not obtained clinical benefit until the clinical data collection date, the ORR was 55.6% (15 / 27), the DCR was 96.3% (26 / 27); the 6-month PFS rate was 86.3%, the median TTR was 1.4 months, and the 6-month DOR rate was 100%. The results show that the anti-HER2 antibody drug conjugate of the present disclosure has good efficacy on patients with biliary tract cancer and shows expected safety in clinical trials.

Claims

1. An anti-HER2 antibody drug conjugate for use in the treatment of biliary tract cancer in a subject, wherein, The anti-HER2 antibody drug conjugate is of the following formula Ia the drug-linker of the structure shown is attached to an antigen binding construct targeting HER2, position 3 of -(succinimid-3-yl-N)- in Formula la is attached to an antigen binding construct targeting HER2, the antigen binding construct targeting HER2 comprises a first antigen binding fragment comprising: a HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 1, a HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 2, a HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 3, a LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 4, a LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 5, and a LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 6, and a second antigen binding fragment comprising: a HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 9, a HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 10, a HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 11, a LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 13, and a LCDR3 comprising the amino acid sequence set forth in SEQ ID NO:

14.

2. The anti-HER2 antibody drug conjugate for use in the treatment of biliary tract cancer in a subject according to claim 1, wherein, the average number of drug-linker attachments per antigen binding construct targeting HER2 is 4 to 7, 5 to 6, or 5.5 to 6.

3. The anti-HER2 antibody drug conjugate for use in the treatment of biliary tract cancer in a subject according to claim 1 or 2, wherein, (i) the first antigen binding fragment comprises a heavy chain variable region having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 7; (ii) the first antigen binding fragment comprises a light chain variable region having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 8; (iii) the first antigen binding fragment comprises a heavy chain variable region having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 7, and a light chain variable region having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 8; (iv) the second antigen binding fragment comprises a heavy chain variable region having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 15; (v) the second antigen binding fragment comprises a light chain variable region having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 16; (vi) the second antigen binding fragment comprises a heavy chain variable region having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 15, and a light chain variable region having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 16; or (vii) the first antigen binding fragment comprises a heavy chain variable region having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 7, and a light chain variable region having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 8; and, the second antigen binding fragment comprises a heavy chain variable region having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 15, and a light chain variable region having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO:

16.

4. The anti-HER2 antibody drug conjugate for use in the treatment of a biliary tract cancer in a subject according to any one of claims 1-3, wherein, (i) the HER2-targeting antigen binding construct comprises a first polypeptide chain having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 17 or 20; (ii) the HER2-targeting antigen binding construct comprises a second polypeptide chain having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 18 or 21; (iii) the HER2-targeting antigen binding construct comprises a third polypeptide chain having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 19; (iv) the HER2-targeting antigen binding construct comprises a first polypeptide chain having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 17 or 20, a second polypeptide chain having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 18 or 21, and a third polypeptide chain having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 19; (iv) the HER2-targeting antigen binding construct comprises a first polypeptide chain having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 17 or 20, a second polypeptide chain having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 18 or 21, and a third polypeptide chain having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 19; (vi) the HER2-targeting antigen binding construct comprises a first polypeptide chain having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO:20, a second polypeptide chain having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO:21, and a third polypeptide chain having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO:19; (vii) the HER2-targeting antigen binding construct comprises a first polypeptide chain having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO:17, a second polypeptide chain having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO:21, and a third polypeptide chain having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO:19; or (viii) the antigen binding construct targeting HER2 comprises a first polypeptide chain having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 20, a second polypeptide chain having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 18, and a third polypeptide chain having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO:

19.

5. The anti-HER2 antibody drug conjugate for use in the treatment of biliary tract cancer in a subject according to any one of claims 1-4, wherein, the anti-HER2 antibody drug conjugate is administered at a dose of 1.5-9 mg / kg, 4.5-7.5 mg / kg, 4.5-6 mg / kg, 5.4-7.5 mg / kg, or 6-7.5 mg / kg per dose; preferably, the anti-HER2 antibody drug conjugate is administered at a dose of 6-7.5 mg / kg per dose, or the anti-HER2 antibody drug conjugate is administered at a dose of 1.5 mg / kg, 3 mg / kg, 4.5 mg / kg, 5.4 mg / kg, 6 mg / kg, 7.5 mg / kg, or 9 mg / kg per dose.

6. The anti-HER2 antibody drug conjugate for use in the treatment of biliary tract cancer in a subject according to any one of claims 1-5, wherein, the anti-HER2 antibody drug conjugate is administered once every 1 week, once every 2 weeks, once every 3 weeks, or once every 4 weeks; preferably, the anti-HER2 antibody drug conjugate is administered once every 3 weeks.

7. The anti-HER2 antibody drug conjugate for use in the treatment of biliary tract cancer in a subject according to any one of claims 1-6, wherein, the anti-HER2 antibody drug conjugate is formulated as a preparation for intravenous injection or infusion; preferably, the administration of the anti-HER2 antibody drug conjugate is performed as intravenous infusion.

8. The anti-HER2 antibody drug conjugate for use in the treatment of biliary tract cancer in a subject according to any one of claims 1-7, wherein, the biliary tract cancer is locally advanced biliary tract cancer; the biliary tract cancer is recurrent biliary tract cancer; the biliary tract cancer is metastatic biliary tract cancer; and / or the biliary tract cancer is unresectable biliary tract cancer.

9. The anti-HER2 antibody drug conjugate for use in the treatment of biliary tract cancer in a subject according to any one of claims 1-8, wherein, the biliary tract cancer is unresectable locally advanced and / or metastatic biliary tract cancer.

10. The anti-HER2 antibody drug conjugate for use in the treatment of biliary tract cancer in a subject according to any one of claims 1-9, wherein, the biliary tract cancer is a HER2 expressing, amplifying, or mutant biliary tract cancer; optionally, the biliary tract cancer is a HER2 positive biliary tract cancer.

11. The anti-HER2 antibody drug conjugate for use in the treatment of biliary tract cancer in a subject according to claim 10, wherein, the HER2 positive biliary tract cancer is a biliary tract cancer in which the expression of HER2 is determined to be 3+ by IHC; or the HER2 positive biliary tract cancer is a biliary tract cancer in which the expression of HER2 is determined to be 2+ by IHC and the expression of HER2 is determined to be positive by ISH.

12. The anti-HER2 antibody drug conjugate for use in the treatment of biliary tract cancer in a subject according to any one of claims 1-11, wherein, the subject with the biliary tract cancer has previously received at least one line of treatment for the biliary tract cancer, preferably, the subject with the biliary tract cancer has previously received at least one line of chemotherapy for the biliary tract cancer; Optionally, the subject with biliary tract cancer has been previously treated with gemcitabine, a platinum drug, and / or a fluorouracil drug for biliary tract cancer. Optionally, the subject is a subject with HER2-positive locally advanced or metastatic biliary tract cancer who has failed first-line chemotherapy.

13. The anti-HER2 antibody drug conjugate for use in the treatment of biliary tract cancer in a subject according to any one of claims 1-12, wherein, The anti-HER2 antibody drug conjugate is used for second-line or more line treatment of biliary tract cancer in a subject.

14. The anti-HER2 antibody drug conjugate for use in the treatment of biliary tract cancer in a subject according to any one of claims 1-13, wherein, The biliary tract cancer is cholangiocarcinoma or gallbladder cancer.

15. The anti-HER2 antibody drug conjugate for use in the treatment of biliary tract cancer in a subject according to any one of claims 1-14, wherein, The biliary tract cancer is intrahepatic cholangiocarcinoma, perihilar cholangiocarcinoma, or distal cholangiocarcinoma.

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