Use of Anti-her2 antibody-drug conjugate in treatment of non-small cell lung cancer

Abstract

The present disclosure belongs to the field of biomedicine, and relates to the use of an anti-HER2 antibody-drug conjugate in the treatment of non-small cell lung cancer. The present disclosure further relates to the use of the anti-HER2 antibody-drug conjugate in the preparation of a drug for treating non-small cell lung cancer in a subject. The present disclosure further relates to a method for treating non-small cell lung cancer in a subject. The method comprises administering the anti-HER2 antibody-drug conjugate to the subject. The method produces benefits for subjects with non-small cell lung cancer and has good safety.

Description

Use of anti-HER2 antibody drug conjugate in treating non-small cell lung 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 non-small cell lung 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 is a widely expressed receptor protein, and abnormal amplification of its gene leads to overexpression of the protein, which in turn causes abnormal activation of the signal pathway, and 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, leading to phosphorylation of receptor tyrosine residues and activation of 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 non-small cell lung cancer, and therefore there is an urgent need to explore drugs targeting HER2 to meet the huge demand for the treatment of non-small cell lung cancer in the clinic. SUMMARY

[0004] Therapeutic methods and uses

[0005] The present disclosure provides a method of treating non-small cell lung 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 non-small cell lung cancer in a subject as a 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 manufacture of a medicament for treating non-small cell lung cancer in a subject. The present disclosure also provides use of an anti-HER2 antibody drug conjugate of the present disclosure in the manufacture of a medicament for treating non-small cell lung cancer in a subject as a 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 uses of an anti-HER2 antibody drug conjugate of the present disclosure for treating non-small cell lung cancer in a subject. The present disclosure also provides uses of an anti-HER2 antibody drug conjugate of the present disclosure for second line or more line treatment of non-small cell lung cancer in a subject. In some embodiments, the uses, the anti-HER2 antibody drug conjugate is administered in a therapeutically effective amount.

[0008] 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, 5-7.5 mg / kg, or 6-7.5 mg / kg per administration. 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 mg / kg, 5.4 mg / kg, 6 mg / kg, 7.5 mg / kg, 9 mg / kg, or a range formed by any two of the foregoing values, per administration. 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 administration. In some embodiments, in the method or use, the anti-HER2 antibody drug conjugate is administered at a dose of 6 mg / kg per administration. 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 administration. 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, 5-7.5 mg / kg, or 6-7.5 mg / kg of the anti-HER2 antibody drug conjugate per administration. 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 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 administration. 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 administration. 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 administration. 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 administration.

[0009] In some embodiments, the method or use is one in which each 1 week, each 2 weeks, each 3 weeks, or each 4 weeks is a treatment cycle. In some embodiments, the method or use is one in which each 3 weeks is a treatment cycle. In some embodiments, the method or use is one in which each 1 week, each 2 weeks, each 3 weeks, or each 4 weeks is a treatment cycle, and the anti-HER2 antibody drug conjugate is administered once per treatment cycle. In some embodiments, the method or use is one in which each 3 weeks is a treatment cycle, and the anti-HER2 antibody drug conjugate is administered once per treatment cycle. In some embodiments, the method or use is one in which each 3 weeks is a treatment cycle, and 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 is one in which each 3 weeks is a treatment cycle, and 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 is one in which each 3 weeks is a treatment cycle, and 6 mg / kg of the anti-HER2 antibody drug conjugate is administered per treatment cycle. In some embodiments, the method or use is one in which each 3 weeks is a treatment cycle, and 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 is one in which each 3 weeks is a treatment cycle, and 7.5 mg / kg of the anti-HER2 antibody drug conjugate is administered per treatment cycle. In some embodiments, the method or use is one in which each 3 weeks is a treatment cycle, and 7.5 mg / kg of the anti-HER2 antibody drug conjugate is administered on day 1 per treatment cycle.

[0010] 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 particular embodiments, the anti-HER2 antibody drug conjugate is formulated into a formulation for intravenous or intramuscular administration. In some particular embodiments, the anti-HER2 antibody drug conjugate can be formulated into an injection. In some particular embodiments, the anti-HER2 antibody drug conjugate is formulated into a formulation for intravenous injection or infusion.

[0011] In some embodiments, in the method or use, the administration of the anti-HER2 antibody drug conjugate is performed using intravenous infusion (also referred to as "intravenous drip").

[0012] In some embodiments, the non-small cell lung cancer is unresectable, refractory, locally advanced, advanced, recurrent, and / or metastatic non-small cell lung cancer. In some embodiments, the non-small cell lung cancer is unresectable non-small cell lung cancer. In some embodiments, the non-small cell lung cancer is refractory non-small cell lung cancer. In some embodiments, the non-small cell lung cancer is locally advanced non-small cell lung cancer. In some embodiments, the non-small cell lung cancer is stage IIIB or stage IIIC non-small cell lung cancer. In some embodiments, the non-small cell lung cancer is advanced non-small cell lung cancer. In some embodiments, the non-small cell lung cancer is recurrent and / or metastatic non-small cell lung cancer. In some embodiments, the non-small cell lung cancer is stage IV non-small cell lung cancer.

[0013] In some embodiments, the non-small cell lung cancer is non-small cell lung cancer with an abnormality in the HER2 gene or other HER family genes (e.g., EGFR gene).

[0014] In some embodiments, the non-small cell lung cancer is a non-small cell lung cancer with an abnormality in the HER2 gene. In some embodiments, the non-small cell lung cancer is a non-small cell lung cancer with overexpression of HER2. In some embodiments, the non-small cell lung cancer is a non-small cell lung cancer with amplification of HER2. In some embodiments, the non-small cell lung cancer is a non-small cell lung cancer with a mutation in HER2. In some embodiments, the non-small cell lung cancer is a non-small cell lung cancer with overexpression, amplification, and / or a mutation in HER2. In some embodiments, the non-small cell lung cancer is a non-small cell lung cancer with overexpression, amplification, or a mutation in HER2. In some embodiments, the non-small cell lung cancer is a non-small cell lung cancer with overexpression or amplification, but not a mutation in HER2. In some embodiments, the non-small cell lung cancer is a non-small cell lung cancer with overexpression, but not a mutation in HER2. In some embodiments, the overexpression of HER2 is determined to be IHC 3+ or IHC 2+ by HER2 testing by immunohistochemistry (IHC). In some embodiments, the non-small cell lung cancer with overexpression of HER2 is a non-small cell lung cancer determined to be IHC 3+ by HER2 testing by IHC. In some embodiments, the non-small cell lung cancer with overexpression of HER2 is a non-small cell lung cancer determined to be IHC 2+ by HER2 testing by IHC.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.

[0015] In some embodiments, the non-small cell lung cancer is EGFR-mutated non-small cell lung cancer. In some embodiments, the EGFR mutation is an EGFR exon 19 deletion mutation. In some embodiments, the EGFR mutation is an EGFR exon 21 L858R mutation. In some embodiments, the EGFR mutation is an EGFR exon 20 insertion mutation.

[0016] In some embodiments, the non-small cell lung cancer is HER2-overexpressing, HER2- amplified, and / or HER2-mutated unresectable non-small cell lung cancer. In some embodiments, the non-small cell lung cancer is HER2-overexpressing, HER2-amplified, and / or HER2-mutated locally advanced non-small cell lung cancer. In some embodiments, the non-small cell lung cancer is HER2-overexpressing, HER2-amplified, and / or HER2-mutated advanced non-small cell lung cancer. In some embodiments, the non-small cell lung cancer is HER2-overexpressing, HER2-amplified, and / or HER2-mutated recurrent and / or metastatic non-small cell lung cancer. In some embodiments, the non-small cell lung cancer is HER2-overexpressing, HER2-amplified, or HER2-mutated unresectable non-small cell lung cancer. In some embodiments, the non-small cell lung cancer is HER2-overexpressing, HER2-amplified, or HER2-mutated locally advanced non-small cell lung cancer. In some embodiments, the non-small cell lung cancer is HER2-overexpressing, HER2-amplified, or HER2-mutated advanced non-small cell lung cancer. In some embodiments, the non-small cell lung cancer is HER2-overexpressing, HER2-amplified, or HER2-mutated recurrent and / or metastatic non-small cell lung cancer. In some embodiments, the non-small cell lung cancer is HER2-overexpressing unresectable non-small cell lung cancer. In some embodiments, the non-small cell lung cancer is HER2-overexpressing locally advanced non-small cell lung cancer. In some embodiments, the non-small cell lung cancer is HER2-overexpressing advanced non-small cell lung cancer. In some embodiments, the non-small cell lung cancer is HER2-overexpressing recurrent and / or metastatic non-small cell lung cancer.

[0017] In some embodiments, the non-small cell lung cancer is EGFR-mutated unresectable non-small cell lung cancer. In some embodiments, the non-small cell lung cancer is EGFR-mutated locally advanced non-small cell lung cancer. In some embodiments, the non-small cell lung cancer is EGFR-mutated advanced non-small cell lung cancer. In some embodiments, the non-small cell lung cancer is EGFR-mutated recurrent and / or metastatic non-small cell lung cancer.

[0018] In some embodiments, the subject with non-small cell lung cancer is not eligible to receive surgery and / or definitive concurrent chemoradiation to treat non-small cell lung cancer. In some embodiments, the subject with locally advanced non-small cell lung cancer is not eligible to receive surgery and / or definitive concurrent chemoradiation to treat non-small cell lung cancer. In some embodiments, the subject with recurrent and / or metastatic non-small cell lung cancer is not eligible to receive surgery and / or definitive concurrent chemoradiation to treat non-small cell lung cancer.

[0019] In some embodiments, the non-small cell lung cancer is locally advanced non-small cell lung cancer that is not eligible to receive surgery and definitive concurrent chemoradiation. In some embodiments, the non-small cell lung cancer is advanced non-small cell lung cancer that is not eligible to receive surgery and definitive concurrent chemoradiation. In some embodiments, the non-small cell lung cancer is recurrent and / or metastatic non-small cell lung cancer that is not eligible to receive surgery and definitive concurrent chemoradiation.

[0020] In some embodiments, the subject with non-small cell lung cancer has been previously treated for non-small cell lung cancer (e.g., failed treatment or was intolerant). In some embodiments, the subject with non-small cell lung cancer has been previously treated with at least one line of therapy to treat non-small cell lung cancer (e.g., failed treatment or was intolerant). In some embodiments, the subject with non-small cell lung cancer has been previously treated with a standard therapy to treat non-small cell lung cancer (e.g., failed treatment or was intolerant). In some embodiments, the subject with non-small cell lung cancer is a subject with locally advanced, recurrent, or metastatic non-small cell lung cancer who was previously treated with a standard therapy but failed treatment, who is not eligible to receive surgery and definitive concurrent chemoradiation.

[0021] Anti-HER2 antibody drug conjugates

[0022] The anti-HER2 antibody drug conjugates used in the present disclosure are linked by a drug-linker of the structure shown in Formula la,

[0023] wherein,

[0024] the 3-position (i.e., the position of attachment) of -(succinimid-3-yl-N)- in Formula la is attached to the HER2-targeting antigen binding construct,

[0025] ​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.

[0026] 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.

[0027] 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.

[0028] Table 1. Exemplary CDR sequences of the antigen binding construct targeting HER2

[0029] 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.

[0030] 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.

[0031] 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.

[0032] 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 framework region (FR).

[0033] 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 specific 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.

[0034] 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.

[0035] 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.

[0036] 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.

[0037] 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.

[0038] 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.

[0039] 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 or constant region, as compared to the amino acid sequence set forth in SEQ ID NO: 17, 18, or 19.

[0040] 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.

[0041] 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.

[0042] The anti-HER2 antibody drug conjugate used in the present disclosure can also be represented by the structure shown in Formula II:

[0043] 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.

[0044] The antibody drug conjugate preferably used in the present disclosure is connected by a drug-linker with the structure shown in formula Ia,

[0045] wherein,

[0046] the 3-position of -(succinimid-3-yl-N)- in formula Ia is connected with the HER2-targeting antigen binding construct,

[0047] the HER2-targeting antigen binding construct consists 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

[0048] For 1 HER2-targeting antigen binding construct, the average number of drug-linker connections is 5 to 6.

[0049] In some embodiments, the 3-position of -(succinimid-3-yl-N)- in formula Ia is connected with the HER2-targeting antigen binding construct through a thioether bond.

[0050] The antibody drug conjugate preferably used in the present disclosure can also be represented by the structure shown in formula II:

[0051] wherein n is 5 to 6,

[0052] 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 via a thioether linkage.

[0053] In other 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.

[0054] 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.

[0055] Pharmaceutical compositions of anti-HER2 antibody drug conjugates

[0056] In some embodiments, the anti-HER2 antibody drug conjugate is formulated as a preparation for administration by parenteral routes. In some specific embodiments, the anti-HER2 antibody drug conjugate is formulated as a preparation for intravenous administration, e.g., for injection or infusion.

[0057] In some embodiments, the anti-HER2 antibody drug conjugate is formulated with one or more pharmaceutically acceptable excipients to make a suitable pharmaceutical composition. Pharmaceutically acceptable excipients include, for example, excipients, diluents, encapsulating materials, fillers, buffers, or other agents.

[0058] In some embodiments, the unit dose of the pharmaceutical composition of the anti-HER2 antibody drug conjugate is 50-600 mg, 100-400 mg, or 100-200 mg of the anti-HER2 antibody drug conjugate, for example, 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, or 600 mg, or a range formed by any two of the aforementioned values.

[0059] In some specific embodiments, the pharmaceutical composition of the anti-HER2 antibody drug conjugate is an injection. In some specific embodiments, the pharmaceutical composition of the anti-HER2 antibody drug conjugate is an aqueous injection, including but not limited to a non-lyophilized aqueous formulation or a reconstituted aqueous formulation of a lyophilized powder.

[0060] In some specific embodiments, the pharmaceutical composition of the anti-HER2 antibody drug conjugate is a powder injection. In some specific embodiments, the pharmaceutical composition of the anti-HER2 antibody drug conjugate is a lyophilized formulation (e.g., a lyophilized powder injection). The lyophilized formulation refers to a formulation prepared from an aqueous solution that has been subjected to a lyophilization process in which the material is first frozen and then the amount of solvent is reduced by sublimation (primary drying process) and then by desorption (secondary drying process) until the amount of solvent is reduced to a value that no longer supports biological activity or chemical reactions. The lyophilized formulation of the present disclosure can also be dried by other methods known in the art, such as spray drying and bubble drying.

[0061] Technical effects

[0062] The administration of the anti-HER2 antibody drug conjugate of the present disclosure has one or several of the following effects:

[0063] (1) produces a benefit in a subject with non-small cell lung cancer, preferably locally advanced, recurrent and / or metastatic non-small cell lung cancer, more preferably locally advanced, recurrent and / or metastatic non-small cell lung cancer with HER2 overexpression, HER2 amplification or HER2 mutation, or EGFR mutation;

[0064] (2) has good safety;

[0065] (3) has good tolerability in a subject.

[0066] Definitions and Descriptions

[0067] The following terms used in the present disclosure have the following meanings unless otherwise specified. A particular term should not be construed as indefinite or unclear if not specifically defined, but should be understood according to 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 its active ingredient.

[0068] As used herein, the structure of “-(succinimid-3-yl-N)-” is as follows:

[0069] Unless otherwise indicated, a solid wedge-shaped bond and a dashed wedge-shaped bond indicate the absolute configuration of a stereocenter.

[0070] Unless otherwise specified, when a group has available sites for attachment, the attachment of the group to other groups can be indicated by a wavy line .

[0071] As used herein, “HER2 mutations” include, but are not limited to, exon 20 insertion mutations and single base pair substitution mutations.

[0072] An "exon 20 insertion mutation" refers to a HER2 mutation caused by base pair insertion into exon 20 of the HER2 gene. Specific examples include, but are not limited to, duplication of the amino acid sequence YVMA at positions 772 to 775 of the HER2 protein (Y772_A775dup, also designated as A775_G776insYVMA, i.e., insertion of the amino acid sequence YVMA between A at position 775 and G at position 776 of the HER2 protein), duplication of the amino acid sequence GSP at positions 778 to 780 of the HER2 protein (G778_P780dup, also designated as P780_Y781insGSP, i.e., insertion of the amino acid sequence GSP between P at position 780 and Y at position 781 of the HER2 protein), substitution of G at position 776 of the HER2 protein with VC (G776delinsVC or G776>VC), insertion of the amino acid sequence AYVM between E at position 770 and A at position 771 of the HER2 protein (E770_A771insAYVM), insertion of the amino acid sequence YVMA between A at position 771 and Y at position 772 of the HER2 protein (A771_Y772insYVMA), insertion of the amino acid sequence AYVM between M at position 774 and A at position 775 of the HER2 protein (M774_A775insAYVM), substitution of G at position 776 of the HER2 protein with LC (G776delinsLC, also designated as G776>LC), substitution of G at position 776 of the HER2 protein with AVGC (G776delinsAVGC, also designated as G776>AVGC), substitution of G at position 776 of the HER2 protein with VV (G776delinsVV, also designated as G776>VV), insertion of a leucine between G at position 776 and V at position 777 of the HER2 protein (G776_V777insL), insertion of VC between G at position 776 and V at position 777 of the HER2 protein (G776_V777insVC), insertion of the amino acid sequence VGC between G at position 776 and V at position 777 of the HER2 protein (G776_V777insVGC), insertion of CG between V at position 777 and G at position 778 of the HER2 protein (V777_G778insCG), insertion of a glycine between V at position 777 and G at position 778 of the HER2 protein (V777_G778insG), insertion of a glycine between G at position 778 and S at position 779 of the HER2 protein (G778_S779insG), or insertion of the amino acid sequence VGS between S at position 779 and P at position 780 of the HER2 protein (S779_P780insVGS), preferably Y772_A775dup, G778_P780dup, or G776delinsVC.

[0073] A "single base pair substitution mutation" refers to a HER2 mutation resulting from the substitution of one base pair of the HER2 gene with another base pair. Specific examples include, but are not limited to, 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* (deletion of W at position 906 of the HER2 protein), T917S, Q943*, S1007*, and S1151L of the HER2 protein, preferably L755S, V777L, V659E, G660D, or S310F.

[0074] 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.

[0075] 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.

[0076] The term "identity" is also referred to as identity. The "percent (%) identity" of an amino acid sequence refers to the percentage of amino acid residues in the sequence to be aligned that are identical with the particular amino acid sequence shown herein, after aligning the sequences to be compared and introducing gaps, if necessary, to achieve the maximum percent sequence identity, and not considering any conservative changes as part of the sequence identity. Amino acid sequence alignment for identity can be performed in a variety of ways within the skill in the art. The skilled artisan can determine appropriate parameters for aligning sequences, including any algorithm that will obtain the maximum alignment over the entire length of the sequences being compared.

[0077] 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:

[0078] (i) preventing a disease or disease state from occurring in a mammal, in particular, when such mammal is predisposed or has yet to be diagnosed as having the disease state;

[0079] (ii) inhibiting the disease or condition, i.e., arresting its development;

[0080] (iii) relieving the disease or condition, i.e., causing regression of the disease or condition;

[0081] (iv) reducing any direct or indirect pathological consequences of the disease or condition.

[0082] The term "therapeutically effective amount" means an amount of a compound of the 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 disclosure that will constitute a "therapeutically effective amount" will vary depending on, among other factors, 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, gender, and weight of the mammal to be treated.

[0083] The terms "administer," "administering," or "administration" mean the physical introduction of a therapeutic agent to a subject using any of a variety of methods and delivery systems known to those skilled in the art.

[0084] 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, subcuticular, 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.

[0085] The term "pharmaceutically acceptable" refers to those compounds, materials, compositions, and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0086] The term "pharmaceutically acceptable salt" refers to a salt of a compound (e.g., an antibody drug conjugate of the disclosure) that is safe and effective for use in the mammalian body and has the appropriate 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.

[0087] The term "excipient" refers to any ingredient other than the active ingredient (e.g., the 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 the excipient should have on solubility and stability, and the nature of the dosage form.

[0088] The term "solvate" refers to a compound associated with a solvent molecule.

[0089] The non-small cell lung cancer "overexpressing HER2" in the present disclosure is not particularly limited as long as it is a non-small cell lung cancer overexpressing HER2 recognized by those skilled in the art, and is preferably a non-small cell lung cancer determined as IHC 3+ or IHC 2+ by HER2 detection by immunohistochemistry (IHC).

[0090] The terms "subject," "patient," or "host" are used interchangeably herein. A "subject," "patient," or "host" includes any human or non-human animal. 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.

[0091] 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.

[0092] The words "comprise," "comprises," or "comprising" and variations thereof, such as "comprises" or "comprising," are to be interpreted consistently with the open, non- exclusive meaning of the term "include" in the broadest sense and are intended to be open-ended, not limiting.

[0093] In this document, the singular forms "a," "an," and "the" include plural references unless the context clearly dictates otherwise.

[0094] As used herein, "about" means within the acceptable error range of a person of ordinary skill in the art judging based on the function involved, that is, within values that the person of ordinary skill in the art operating standard equipment and known techniques can represent. For example, "about" can mean within 1 or more than 1 standard deviation per the practice in the art. Alternatively, "about" can mean up to ± 5% of a given value, such as within ± 2% of a given value, within ± 1% of a given value, or within ± 0.5% of a given value. When a particular value is given in the disclosure or claims, the meaning of "about" should be considered to be within the acceptable error range of the particular value unless otherwise stated. In this document, all values for dosage, time, step parameters, or conditions of a method are default modified by "about" unless otherwise indicated.

[0095] For the purposes of description and disclosure, all patents, patent applications, and other publications identified herein are expressly incorporated herein by reference. Such publications are provided solely for their disclosure prior to the filing date of the present disclosure. All statements as to the date or contents of these publications are based on the information available to the applicants and do not constitute any admission as to the correctness of the dates or contents of these publications. Further, nothing herein is to be construed as an admission that the publications are part of the state of the art or are common general knowledge.

[0096] The present disclosure also provides some specific embodiments as follows, but the scope of protection of the present disclosure is not limited thereto:

[0097] Embodiment 1. A method of treating non-small cell lung 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 Ia

[0098] the drug-linker of the structure shown is connected to an antigen-binding construct targeting HER2,

[0099] the 3-position of -(succinimid-3-yl-N)- in formula Ia is connected to an antigen-binding construct targeting HER2,

[0100] 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.

[0101] 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.

[0102] 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.

[0103] 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.

[0104] Embodiment 5. The method of any one of embodiments 1-4, wherein,

[0105] (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;

[0106] (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;

[0107] (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;

[0108] (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;

[0109] (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;

[0110] (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

[0111] (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.

[0112] Embodiment 6. The method of any one of embodiments 1-5, wherein,

[0113] (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;

[0114] (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;

[0115] (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;

[0116] (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;

[0117] (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;

[0118] (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;

[0119] (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

[0120] (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.

[0121] Embodiment 7. The method of any one of claims 1-6, wherein the anti-HER2 antibody drug conjugate is formulated with one or more pharmaceutically acceptable excipients into a pharmaceutical composition, the unit dose of which is 50-600 mg, 100-400 mg, or 100-200 mg of the anti-HER2 antibody drug conjugate; preferably, the unit dose of the pharmaceutical composition is 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, and / or 600 mg of the anti-HER2 antibody drug conjugate; more preferably, the unit dose of the pharmaceutical composition is 100 mg of the anti-HER2 antibody drug conjugate.

[0122] Embodiment 8. The method of any one of embodiments 1-7, wherein the anti-HER2 antibody drug conjugate is administered in a therapeutically effective amount.

[0123] Embodiment 9. The method of any one of embodiments 1-8, wherein the anti-HER2 antibody drug conjugate is administered each time at a dose of 1.5-9 mg / kg, 5-7.5 mg / kg, or 6-7.5 mg / kg; preferably, the anti-HER2 antibody drug conjugate is administered each time at a dose of 6-7.5 mg / kg.

[0124] Embodiment 10. The method of embodiment 9, wherein the anti-HER2 antibody drug conjugate is administered each time at a dose of 1.5 mg / kg, 3 mg / kg, 4.5 mg / kg, 5 mg / kg, 5.4 mg / kg, 6 mg / kg, 7.5 mg / kg, or 9 mg / kg; preferably, the anti-HER2 antibody drug conjugate is administered each time at a dose of 6 mg / kg or 7.5 mg / kg.

[0125] Embodiment 11. The method of any one of embodiments 1-10, 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.

[0126] Embodiment 12. The method of any one of claims 1-11, wherein the anti-HER2 antibody drug conjugate is administered once every 3 weeks at a dose of 6 mg / kg or 7.5 mg / kg each time; preferably, the anti-HER2 antibody drug conjugate is administered once every 3 weeks at a dose of 7.5 mg / kg each time.

[0127] Embodiment 13. The method of any one of embodiments 1-12, wherein the anti-HER2 antibody drug conjugate is formulated as a formulation for intravenous injection or infusion.

[0128] Embodiment 14. The method of any one of embodiments 1-13, wherein the administration of the anti-HER2 antibody drug conjugate is by intravenous infusion.

[0129] Embodiment 15. The method of any one of claims 1-14, wherein each 3 weeks is a treatment cycle.

[0130] Embodiment 16. The method of any one of embodiments 1-15, wherein the non-small cell lung cancer is locally advanced non-small cell lung cancer.

[0131] Embodiment 17. The method of any one of embodiments 1-15, wherein the non-small cell lung cancer is stage IIIB or stage IIIC non-small cell lung cancer.

[0132] Embodiment 18. The method of any one of embodiments 1-15, wherein the non-small cell lung cancer is recurrent and / or metastatic non-small cell lung cancer.

[0133] Embodiment 19. The method of any one of embodiments 1-15, wherein the non-small cell lung cancer is stage IV non-small cell lung cancer.

[0134] Embodiment 20. The method of any one of embodiments 1-19, wherein the non-small cell lung cancer is a non-small cell lung cancer that is HER2 overexpressing, HER2 amplifying, and / or HER2-mutated.

[0135] Embodiment 21. The method of embodiment 20, wherein the HER2 overexpression is a HER2 detection by IHC that is determined to be IHC 3+ or IHC 2+.

[0136] Embodiment 22. The method of embodiment 20, wherein the HER2 mutation is an exon 20 insertion mutation or a single base pair substitution mutation.

[0137] Embodiment 23. The method of embodiment 20, wherein 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.

[0138] Embodiment 24. The method of embodiment 23, wherein the HER2 mutation is at least one selected from the group consisting of Y772_A775dup, G778_P780dup, G776delinsVC, L755S, V777L, V659E, G660D, and S310F.

[0139] Embodiment 25. The method of any one of embodiments 1-24, wherein the non-small cell lung cancer is EGFR-mutated non-small cell lung cancer.

[0140] EGFR exon 20 insertion mutation.

[0141] Embodiment 27. The method of any one of embodiments 1-26, wherein the subject with non-small cell lung cancer has been previously treated for non-small cell lung cancer.

[0142] Embodiment 28. The method of embodiment 27, wherein the subject with non-small cell lung cancer has been previously treated for non-small cell lung cancer with a standard therapy.

[0143] Embodiment 29. The method of any one of embodiments 1-28, wherein the subject with non-small cell lung cancer is not eligible for surgery and / or radical concurrent chemoradiation to treat non-small cell lung cancer.

[0144] Embodiment 30. The method of any one of embodiments 1-29, wherein the anti-HER2 antibody drug conjugate is used in the treatment of non-small cell lung cancer in the subject as a second line or more line of therapy.

[0145] Embodiment 31. Use of an anti-HER2 antibody drug conjugate in the manufacture of a medicament for the treatment of non-small cell lung cancer in a subject, wherein the anti-HER2 antibody drug conjugate is of the formula la

[0146] the drug-linker of the structure shown below,

[0147] the 3-position of -(succinimid-3-yl-N)- in formula la is linked to the antigen binding construct targeting HER2,

[0148] 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.

[0149] Embodiment 32. The use according to embodiment 31, wherein the average number of drug-linker attachments per one antigen binding construct targeting HER2 is from 4 to 7.

[0150] Embodiment 33. The use according to embodiment 32, wherein the average number of drug-linker attachments per one antigen binding construct targeting HER2 is from 5 to 6.

[0151] Embodiment 34. The use according to embodiment 33, wherein the average number of drug-linker attachments per one antigen binding construct targeting HER2 is from 5.5 to 6.

[0152] Embodiment 35. The use according to any one of embodiments 31-34, wherein,

[0153] (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;

[0154] (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;

[0155] (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;

[0156] (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;

[0157] (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;

[0158] (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

[0159] (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.

[0160] Embodiment 36. The use according to any one of embodiments 31-35, wherein,

[0161] (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;

[0162] (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;

[0163] (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;

[0164] (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;

[0165] (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;

[0166] (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;

[0167] (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

[0168] (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.

[0169] Embodiment 37. The use of any one of claims 31-36, wherein the anti-HER2 antibody drug conjugate is formulated with one or more pharmaceutically acceptable excipients into a pharmaceutical composition having a unit dose of 50-600 mg, 100-400 mg, or 100-200 mg of the anti-HER2 antibody drug conjugate; preferably, the unit dose of the pharmaceutical composition is 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, and / or 600 mg of the anti-HER2 antibody drug conjugate; more preferably, the unit dose of the pharmaceutical composition is 100 mg of the anti-HER2 antibody drug conjugate.

[0170] Embodiment 38. The use of any one of embodiments 31-37, wherein the medicament comprises a therapeutically effective amount of the anti-HER2 antibody drug conjugate.

[0171] Embodiment 39. The use of any one of embodiments 31-38, wherein the medicament is formulated to be suitable for administering the anti-HER2 antibody drug conjugate at a dose of 1.5-9 mg / kg, 5-7.5 mg / kg, or 6-7.5 mg / kg each time; preferably, the medicament is formulated to be suitable for administering the anti-HER2 antibody drug conjugate at a dose of 6-7.5 mg / kg each time.

[0172] Embodiment 40. The use of embodiment 39, wherein the medicament is formulated to be suitable for administering the anti-HER2 antibody drug conjugate at a dose of 1.5 mg / kg, 3 mg / kg, 4.5 mg / kg, 5 mg / kg, 5.4 mg / kg, 6 mg / kg, 7.5 mg / kg, or 9 mg / kg each time; preferably, the medicament is formulated to be suitable for administering the anti-HER2 antibody drug conjugate at a dose of 6 mg / kg or 7.5 mg / kg each time.

[0173] Embodiment 41. The use of any one of embodiments 31-40, wherein the anti-HER2 antibody drug conjugate is administered once every 1 week, every 2 weeks, every 3 weeks, or every 4 weeks; preferably, the anti-HER2 antibody drug conjugate is administered once every 3 weeks.

[0174] Embodiment 42. The use of any one of claims 31-38, wherein the anti-HER2 antibody drug conjugate is administered once every 3 weeks at a dose of 6 mg / kg or 7.5 mg / kg each time; preferably, the anti-HER2 antibody drug conjugate is administered once every 3 weeks at a dose of 7.5 mg / kg each time.

[0175] Embodiment 43. The use of any one of embodiments 31-42, wherein the anti-HER2 antibody drug conjugate is formulated as a formulation for intravenous injection or infusion.

[0176] Embodiment 44. The use of any one of embodiments 31-43, wherein administration of the anti-HER2 antibody drug conjugate is by intravenous infusion.

[0177] Embodiment 45. The use of any one of claims 31-44, wherein each 3 weeks is a treatment cycle.

[0178] Embodiment 46. The use of any one of embodiments 31-45, wherein the non-small cell lung cancer is locally advanced non-small cell lung cancer.

[0179] Embodiment 47. The use of any one of embodiments 31-45, wherein the non-small cell lung cancer is stage IIIB or stage IIIC non-small cell lung cancer.

[0180] Embodiment 48. The use of any one of embodiments 31-45, wherein the non-small cell lung cancer is recurrent and / or metastatic non-small cell lung cancer.

[0181] Embodiment 49. The use of any one of embodiments 31-45, wherein the non-small cell lung cancer is stage IV non-small cell lung cancer.

[0182] Embodiment 50. The use of any one of embodiments 31-49, wherein the non-small cell lung cancer is a non-small cell lung cancer that overexpresses HER2, that is amplified for HER2, or that has a HER2 mutation.

[0183] Embodiment 51. The use of embodiment 50, wherein the HER2 overexpression is determined to be IHC 3+ or IHC 2+ by HER2 testing by IHC.

[0184] Embodiment 52. The use of embodiment 50, wherein the HER2 mutation is an exon 20 insertion mutation or a single base pair substitution mutation.

[0185] Embodiment 53. The use according to embodiment 50, wherein 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.

[0186] Embodiment 54. The use according to embodiment 53, wherein the HER2 mutation is at least one selected from the group consisting of Y772_A775dup, G778_P780dup, G776delinsVC, L755S, V777L, V659E, G660D, and S310F.

[0187] Embodiment 55. The use according to any one of embodiments 31-54, wherein the non-small cell lung cancer is EGFR-mutated non-small cell lung cancer.

[0188] Embodiment 56. The use according to Embodiment 55, wherein the EGFR mutation is at least one selected from the group consisting of an EGFR exon 19 deletion mutation, an EGFR exon 21 L858R mutation, and an EGFR exon 20 insertion mutation.

[0189] Embodiment 57. The use according to any one of Embodiments 31-56, wherein the subject with non-small cell lung cancer has been previously treated for non-small cell lung cancer.

[0190] Embodiment 58. The use according to Embodiment 57, wherein the subject with non-small cell lung cancer has been previously treated for non-small cell lung cancer with a standard treatment.

[0191] Embodiment 59. The use according to any one of Embodiments 41-58, wherein the subject with non-small cell lung cancer is not suitable for receiving surgery and / or radical concurrent chemoradiotherapy for treating non-small cell lung cancer.

[0192] Embodiment 60. The use according to any one of Embodiments 41-59, wherein the anti-HER2 antibody drug conjugate is used for treating non-small cell lung cancer in the subject in the second line or more. Examples

[0193] For the sake of clarity, the present disclosure is further explained with examples, which are not intended to limit the scope of the present disclosure.

[0194] The entire contents of WO2022033578 or CN115702008A patent application file are incorporated into the present disclosure. The anti-HER2 antibody drug conjugate in the following examples is prepared according to the preparation method described in WO2022033578, which is an anti-HER2 antibody drug conjugate represented by the following formula (hereinafter referred to as ADC1):

[0195] wherein the drug-linker is connected to the HER2-targeting antigen binding construct through a thioether bond, n is 5 to 6, 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:

[0196] Example 1: Clinical trial of non-small cell lung cancer with abnormal HER2 gene and other HER family genes

[0197] 1. Study objectives:

[0198] 1.1 Phase A

[0199] To evaluate the preliminary effectiveness, safety and immunogenicity of ADC1 in non-small cell lung cancer with abnormal HER2 gene or other HER family genes.

[0200] 1.2 Phase B

[0201] To evaluate the objective response rate (ORR), duration of response (DOR), progression-free survival (FPS), overall survival (OS), safety and immunogenicity of ADC1 in non-small cell lung cancer with abnormal HER2 gene.

[0202] 2. Trial design

[0203] 2.1 Phase A

[0204] Cohort 1: subjects carrying HER2 mutations;

[0205] Cohort 2: subjects carrying HER2 amplification or overexpression without HER2 mutations;

[0206] Cohort 3: subjects carrying EGFR mutations.

[0207] 2.2 Phase B

[0208] Based on the results of clinical research in phase A.

[0209] 3. Inclusion criteria

[0210] Subjects meeting all the following inclusion criteria can be enrolled in this trial:

[0211] (1) Subjects voluntarily join this study, sign the informed consent form, and have good compliance;

[0212] (2) Age: 18-75 years old (at the time of signing the informed consent form); ECOG PS score: 0-1 points; expected survival time more than 3 months;

[0213] (3) Patients with cytological or histological confirmed non-surgical treatment and unable to accept radical concurrent chemoradiotherapy of locally advanced (IIIB / IIIC stage), metastatic or recurrent (IV stage) NSCLC according to the International Association for Lung Cancer Research and the United States Cancer Classification Joint Committee 8th edition lung cancer TNM staging;

[0214] (4) Failure after standard treatment;

[0215] (5) Cohort 1 and Cohort 2 require the presence of HER2 mutations or overexpression (IHC 2+ or IHC 3+) in the sample of subjects within 2 years, Cohort 3 requires subjects carrying EGFR mutations;

[0216] (6) At least one measurable lesion according to RECIST 1.1 criteria, lesions previously treated with radiotherapy cannot be considered target lesions unless there is clear progression of the lesion after radiotherapy (except for skin and / or brain lesions as measurable lesions);

[0217] (7) Good primary organ function, blood routine, biochemical examination, coagulation function examination meet the standard:

[0218] (8) Child-bearing age female subjects should agree to use contraceptive measures (such as intrauterine device, contraceptive drugs or condom) during the study period and 6 months after the end of the study; serum pregnancy test negative within 7 days before study entry, and must be non-lactating subjects; male subjects should agree to use contraceptive measures during the study period and 6 months after the end of the study.

[0219] 4. Test drug

[0220] ADC1 for injection (specification: 100 mg / bottle) is developed and provided by Nanjing Shunxin Pharmaceutical Co., Ltd., Zhejiang Hisun Pharmaceutical Co., Ltd.

[0221] 5. Treatment regimen

[0222] ADC1 is intravenously infused, and the dose is 7.5 mg / kg, every 3 weeks (21 days) for 1 treatment cycle, and ADC1 is administered once every treatment cycle (the administration window period is ± 3 days of the planned administration time), until clinical benefit is lost, toxicity is intolerable, or the investigator considers it inappropriate to continue medication.

[0223] 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.

[0224] 6. Evaluation criteria

[0225] Effectiveness evaluation: RECIST 1.1 criteria is used to determine the disease status.

[0226] Safety evaluation: NCI-CTC AE 5.0 criteria is used to judge the severity of adverse events.

[0227] 7. Endpoint indicators

[0228] 7.1 A phase

[0229] (1) Primary endpoint:

[0230] ORR assessed by the investigator.

[0231] (2) Secondary endpoints:

[0232] Other effectiveness indicators such as duration of remission (DOR), progression-free survival (PFS), overall survival (OS), etc.

[0233] Incidence and severity of adverse events (AEs) and serious adverse events (SAEs), and abnormal laboratory examination indicators;

[0234] Immunogenicity: such as incidence of ADAs, etc.

[0235] 7.2 Phase B

[0236] (1) Primary endpoint:

[0237] ORR assessed by independent image review committee.

[0238] (2) Secondary endpoints:

[0239] Other effectiveness indicators such as ORR assessed by researchers, DOR, PFS, OS, etc.

[0240] Incidence and severity of AEs and SAEs, and abnormal laboratory examination indicators;

[0241] Immunogenicity: such as incidence of ADAs, etc.

[0242] 8. Results

[0243] By the data statistics day, a total of 35 subjects in Cohort 1 reached an assessable degree, of which 23 subjects reached partial remission (PR), and the ORR was 65.7%; a total of 10 subjects in Cohort 2 reached an assessable degree, of which 5 reached PR, and the ORR was 50% (5 / 10); a total of 10 subjects in Cohort 3 reached an assessable degree, of which 9 reached PR, and the ORR was 90% (9 / 10).

[0244] The results show that the anti-HER2 antibody drug conjugate of the present disclosure has good efficacy on non-small cell lung cancer patients with abnormal HER2 gene or other HER family genes (such as EGFR gene), shows low immunogenicity, and shows expected safety in clinical trials.

Claims

1. An anti-HER2 antibody drug conjugate for use in the treatment of non-small cell lung 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 non-small cell lung 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 non-small cell lung 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 non-small cell lung 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; or (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.

5. The anti-HER2 antibody drug conjugate for use in the treatment of non-small cell lung cancer in a subject according to any one of claims 1-4, wherein, The anti-HER2 antibody drug conjugate is formulated into a pharmaceutical composition with one or more pharmaceutically acceptable excipients, the unit dose of the pharmaceutical composition is 50-600 mg, 100-400 mg, or 100-200 mg of the anti-HER2 antibody drug conjugate; preferably, the unit dose of the pharmaceutical composition is 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, and / or 600 mg of the anti-HER2 antibody drug conjugate; more preferably, the unit dose of the pharmaceutical composition is 100 mg of the anti-HER2 antibody drug conjugate.

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

7. The anti-HER2 antibody drug conjugate for use in the treatment of non-small cell lung cancer in a subject according to any one of claims 1-6, 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.

8. The anti-HER2 antibody drug conjugate for use in the treatment of non-small cell lung cancer in a subject according to any one of claims 1-7, wherein, The anti-HER2 antibody drug conjugate is administered once every 3 weeks at a dose of 6 mg / kg or 7.5 mg / kg; preferably, the anti-HER2 antibody drug conjugate is administered once every 3 weeks at a dose of 7.5 mg / kg.

9. The anti-HER2 antibody drug conjugate for use in the treatment of non-small cell lung cancer in a subject according to any one of claims 1-8, 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 by intravenous infusion.

10. The anti-HER2 antibody drug conjugate for use in the treatment of non-small cell lung cancer in a subject according to any one of claims 1-9, wherein, The non-small cell lung cancer is locally advanced non-small cell lung cancer; The non-small cell lung cancer is stage IIIB or stage IIIC non-small cell lung cancer; The non-small cell lung cancer is recurrent and / or metastatic non-small cell lung cancer; or The non-small cell lung cancer is stage IV non-small cell lung cancer.

11. The use according to any one of claims 1 to 10, wherein, The non-small cell lung cancer is non-small cell lung cancer that overexpresses HER2, that amplifies HER2, or that has a HER2 mutation.

12. The use according to claim 11, wherein, The HER2 overexpression is determined to be IHC 3+ or IHC 2+ by HER2 testing by IHC; The HER2 mutation is an exon 20 insertion mutation or a single base pair substitution mutation; or The HER2 mutation is an exon 20 insertion mutation or a single base pair substitution mutation; or 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.

13. Use according to claim 12, wherein, The HER2 mutation is at least one selected from the group consisting of Y772_A775dup, G778_P780dup, G776delinsVC, L755S, V777L, V659E, G660D, and S310F.

14. The use according to any one of claims 1 to 13, wherein, The non-small cell lung cancer is EGFR-mutated non-small cell lung cancer. Preferably, the EGFR mutation is at least one selected from the group consisting of an EGFR exon 19 deletion mutation, an EGFR exon 21 L858R mutation, and an EGFR exon 20 insertion mutation.

15. The use according to any one of claims 1 to 14, wherein, The subject with non-small cell lung cancer has been previously treated for non-small cell lung cancer. Preferably, the subject with non-small cell lung cancer has been previously treated for non-small cell lung cancer. The subject with non-small cell lung cancer is not suitable for receiving surgery and / or radical concurrent chemoradiation to treat non-small cell lung cancer; and / or The anti-HER2 antibody drug conjugate is used in the second line or more line treatment of non-small cell lung cancer in the subject. The anti-HER2 antibody drug conjugate is used in the second line or more line treatment of non-small cell lung cancer in the subject.

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