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NZ785232B2 - Eribulin-based Antibody-Drug Conjugates and Methods of Use - Google Patents
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NZ785232B2 - Eribulin-based Antibody-Drug Conjugates and Methods of Use - Google Patents

Eribulin-based Antibody-Drug Conjugates and Methods of Use

Info

Publication number
NZ785232B2
NZ785232B2 NZ785232A NZ78523217A NZ785232B2 NZ 785232 B2 NZ785232 B2 NZ 785232B2 NZ 785232 A NZ785232 A NZ 785232A NZ 78523217 A NZ78523217 A NZ 78523217A NZ 785232 B2 NZ785232 B2 NZ 785232B2
Authority
NZ
New Zealand
Prior art keywords
antibody
rule
drug conjugate
substitute sheet
seq
Prior art date
Application number
NZ785232A
Other versions
NZ785232A (en
Inventor
Earl F Albone
Xin Cheng
Daniel W Custar
Keiji Furuuchi
Jing Li
Utpal Majumder
Toshimitsu Uenaka
Original Assignee
Eisai R&D Management Co Ltd
Filing date
Publication date
Application filed by Eisai R&D Management Co Ltd filed Critical Eisai R&D Management Co Ltd
Publication of NZ785232A publication Critical patent/NZ785232A/en
Publication of NZ785232B2 publication Critical patent/NZ785232B2/en

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/357—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
    • A61K47/65—Peptidic linkers, binders or spacers, e.g. peptidic enzyme-labile linkers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6801—Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
    • A61K47/6803—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6801—Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
    • A61K47/6803—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
    • A61K47/68031—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates the drug being an auristatin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6801—Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
    • A61K47/6803—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
    • A61K47/68033—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates the drug being a maytansine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
    • A61K47/6849—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a receptor, a cell surface antigen or a cell surface determinant
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6889—Conjugates wherein the antibody being the modifying agent and wherein the linker, binder or spacer confers particular properties to the conjugates, e.g. peptidic enzyme-labile linkers or acid-labile linkers, providing for an acid-labile immuno conjugate wherein the drug may be released from its antibody conjugated part in an acidic, e.g. tumoural or environment
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/30—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants from tumour cells
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/32—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against translation products of oncogenes
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/10—Immunoglobulins specific features characterized by their source of isolation or production
    • C07K2317/14—Specific host cells or culture conditions, e.g. components, pH or temperature
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/40—Immunoglobulins specific features characterized by post-translational modification
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
    • C07K2317/565—Complementarity determining region [CDR]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/77—Internalization into the cell
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
    • C07K2317/92—Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value

Abstract

Linker toxins and antibody-drug conjugates that bind to human oncology antigen targets such as folate receptor alpha and/or provide anti-tubulin drug activity are disclosed. The linker toxins and antibody-drug conjugates comprise an eribulin drug moiety and can be internalized into target antigen-expressing cells. The disclosure further relates to methods and compositions for use in the treatment of cancer by administering the antibody-drug conjugates provided herein.

Claims (29)

CLAIMS DEFINING THE INVENTION ARE AS S:
1. An antibody-drug conjugate of Formula (I): Ab-(L-D)p (I) wherein Ab is an internalizing anti-HER2 antibody or internalizing antigen-binding nt thereof comprising three heavy chain complementarity ining regions ) comprising amino acid sequences of SEQ ID NO:71 (HCDR1), SEQ ID NO:72 (HCDR2), and SEQ ID NO:73 (HCDR3); and three light chain complementarity determining regions ) comprising amino acid sequences of SEQ ID NO:74 (LCDR1), SEQ ID NO:75 (LCDR2), and SEQ ID NO:76 (LCDR3), as defined by the Kabat numbering system; or three heavy chain complementarity determining regions (HCDRs) comprising amino acid sequences of SEQ ID NO:191 (HCDR1), SEQ ID NO:192 (HCDR2), and SEQ ID NO:193 (HCDR3); and three light chain complementarity determining regions (LCDRs) comprising amino acid sequences of SEQ ID NO:194 ), SEQ ID NO:195 (LCDR2), and SEQ ID NO:196 (LCDR3), as defined by the IMGT numbering system; D is eribulin; L is a cleavable linker comprising valine-citrulline (Val-Cit); and p is an r from 1 to 8.
2. The antibody-drug conjugate of claim 1, wherein p is an integer from 1 to 4.
3. The antibody-drug conjugate of claim 1 or claim 2, wherein the cleavable linker further comprises an antibody attachment group and a spacer unit.
4. The antibody-drug conjugate of claim 3, wherein the antibody or antigen-binding fragment is joined to the antibody attachment group.
5. The antibody-drug conjugate of claim 3 or claim 4 , wherein the spacer unit comprises a polyethylene glycol (PEG) .
6. The dy-drug conjugate of claim 5, wherein the PEG moiety comprises -(PEG)mand m is an integer from 1 to 10.
7. The antibody-drug conjugate of claim 6, wherein m is 2.
8. The antibody-drug conjugate of any one of claims 3 to 7, wherein the spacer unit attaches to the antibody or antigen-binding fragment via the antibody attachment group.
9. The antibody-drug conjugate of any one of claims 3 to 8, wherein the antibody ment group ses a maleimide (Mal) moiety (“Mal-spacer unit”).
10. The antibody-drug conjugate of claim 9, wherein the Mal-spacer unit is joined to the antibody or antigen-binding fragment via a cysteine residue on the dy or nbinding fragment.
11. The antibody-drug conjugate of claim 9 or claim 10, wherein the Mal-spacer unit attaches the antibody or antigen-binding fragment to the Val-Cit.
12. The antibody-drug conjugate of any one of claims 3 to 11, wherein the cleavable linker comprises Mal-(PEG)2-Val-Cit.
13. The antibody-drug conjugate of any one of claims 1 to 12, wherein the Val-Cit is joined to eribulin directly or through an additional spacer unit.
14. The antibody-drug conjugate of claim 13, n the onal spacer unit attaching the cleavable unit to eribulin is self-immolative.
15. The antibody-drug conjugate of claim 13 or claim 14, wherein the additional spacer unit attaching the cleavable unit to in comprises a p-aminobenzyloxycarbonyl (pAB).
16. The antibody-drug conjugate of claim 15, wherein the pAB covalently attaches to eribulin via a C-35 amine.
17. The antibody-drug ate of any one of claims 1 to 16, wherein the cleavable linker comprises Val-Cit-pAB.
18. The antibody-drug conjugate of any one of claims 1 to 17, wherein the ble linker comprises Mal-(PEG)2-Val-Cit-pAB.
19. The antibody-drug conjugate of any one of claims 1 to 18, wherein the antibody or antigen-binding fragment comprises a heavy chain variable region comprising an amino acid sequence of SEQ ID NO:27, and a light chain variable region comprising an amino acid sequence of SEQ ID NO:28.
20. The antibody-drug conjugate of any one of claims 1 to 19, wherein the antibody or antigen-binding fragment comprises a human IgG1 heavy chain constant .
21. The antibody-drug conjugate of any one of claims 1 to 20, wherein the antibody or antigen-binding nt comprises a human Ig kappa light chain constant .
22. A composition sing multiple copies of the antibody-drug conjugate of any one of claims 1 to 21, wherein the average p of the antibody-drug conjugates in the composition is from about 3.2 to about 4.4.
23. Use of a therapeutically effective amount of the antibody-drug conjugate of any one of claims 1 to 21 or the composition of claim 22 in the manufacture of a medicament for the ent of a cancer that expresses HER2.
24. The use of claim 23, wherein the HER2-expressing cancer is a c cancer, an ovarian cancer, a lung cancer, a breast cancer, an endometrial cancer, a bladder cancer, an esophageal cancer, a cervical cancer, or an urothelial cell carcinoma.
25. Use of a therapeutically effective amount of the antibody-drug conjugate of any one of claims 1 to 21 or the composition of claim 22 in the manufacture of a medicament for reducing or inhibiting growth of a tumor that expresses HER2.
26. The use of claim 25, wherein the HER2-expressing tumor is a gastric cancer, an ovarian , a lung cancer, a breast cancer, an endometrial cancer, a r , an esophageal cancer, a cervical cancer, or an urothelial cell carcinoma.
27. A pharmaceutical composition comprising the antibody-drug ate of any one of claims 1 to 21, and a pharmaceutically acceptable carrier.
28. An in vitro method of determining whether a patient will be responsive to treatment with the dy-drug conjugate of any one of claims 1 to 21 or the composition of claim 22, the method comprising ting a biological sample from the patient with the antibody-drug conjugate of any one of claims 1 to 21 or the composition of claim
29. A method of producing the antibody-drug conjugate of any one of claims 1 to 21, comprising reacting an antibody or antigen-binding fragment with a cleavable linker joined to eribulin under conditions that allow conjugation. ”3/32 mwm RE .92. wwmm?mmm é?zmm?mma mixno ZEEEEW zomwonwmm $8, 4%va @2me SUBSTITUTE SHEET (RULE 26) W0 2017!]51979 ,wam,m§ 323 mem .w “N SUBSTITUTE SHEET (RULE 26) TUTE SHEET (RULE 26) 260K" -->- 0‘; C3 lax .4. mm C3 :5 CO C) .x O) C? 2‘5 01 CD :5 SUBSTITUTE SHEET (RULE 26) {:3 C} CC} CC} (I) {23 CC} (.Q (D V... CC) £0 LC) w N w"- SUBSTITUTE SHEET (RULE 26) . 35>} Ema.. ?g mma mmm mg 3% Yak? $2 g E; NE ,mmm?nu‘om mg ,wmmma‘og SW mg ,mma?mmioo ex?omwmamfw .mmnmg Gag gomgami gamma zjnmamd?x “Eggnog: New?mognogx ma?a: USN/0%. 30mg;mow?ogiomg -?: Ea... an? gm: ,3. CD CD BNETEEN £62) 0/ l0 SUBSTITUTE SHEET (RULE 26) 3% Em; ME ”ma $9 “MEN Ema. ,wmamawg NE NE E E $3qu “$3.58 "$3.53 Ea 2555ng gamga?xv :65“. m E m E E E E wm wm xm m E E E m mmimgno?m WEEEEEE o?x Emagomg :? EQ; -?a -Ea SNWEM 30 /o SUBSTITUTE SHEET (RULE 26) 3%. 3%. mg mm; ?g mm Em; N ”ma “mm??g g . ,mm?a 232$va ragga; mmgi?ga?x mmgégmgx mwgggggmg o. é... a? ,3- ammm 30 .' SUBSTITUTE SHEET (RULE 26) 2339mm max/imgo?mog moa?mog SUBSTITUTE SHEET (RULE 26) ”ES/32 17.5' EJQQS-0285 E Lt") mAU CC} {:3 «2- (Q ”<3“ N SUBSTITUTE SHEET (RULE 26) ”31,532 maamqmog moo?mom» Elm Elm m- 2725mm +23%me zjnmwmm +zjnmmm? max/-moanqmog?omg aux/-moa?mosgomww m§f s0: BAY Law. -mv... El "Zigzag 5, E6328 SUBSTITUTE SHEET (RULE 26) ”EB/’32 Sompzoowmm @agegm?og Emagsw?é $33 swig?“ ?mgwgm?og go... é, é: $1. a? <6} ag SUBSTITUTE SHEET (RULE 26) ”ES/32 wmm £3233me Ewgwdzgmam Znamam magmmzamam g0... gm; Lg... $2 a? WW7 . .. mammgaxaagag5,2 Emg?? ..... . 9% E if: m w ..... gamma E Exam; Emmwmwrm (6} GOE SUBSTITUTE SHEET (RULE 26) 14KB? 2.3%”; Emgmwgzéog 3% wma ma?a; £33 i? gm, é- g? :0: : , ham—uuuuuuuww { uuuuuuww..-.5 Lnnnnnnumm '4 ........____' human” ¢ .......,_’5 ’”~4g 20? C gwm 3 ammo/Ix aowm SUBSTITUTE SHEET (RULE 26) 15/32 2.: 533:? >.. {5’ g 5%, s2 ”0% E 5’96} C.) CD 0- c2) c2:- _ Lo Q m D N N \-‘ 1-“ (saw) awmexx 30m SUBSTITUTE SHEET (RULE 26) 16f32 a? SEEN 3% mag mmm wage: gm?og “ £3.80 HQ: 3%: $9,! a? a? 3 20%?an mm 2% om gem mm wEm (5) THSEMAGGB SUBSTITUTE SHEET (RULE 26) 5%, g 233mg Emgmdzgmam Eméggnmw? so... ?; 2%: .x... a? ZQENEQmEm wmo?m Q C?) 8E Q C?) D O 0 O W (3) CS) “Q“ N 'r‘ {saw} gimme/x SOLa: SUBSTITUTE SHEET (RULE 26) “38/32 3000 2506 2000 150C 1-300 500 (SW) Mme/x gown; SUBSTITUTE SHEET (RULE 26) ”?g/32 a??? ............................ ........................... _ mmmm ........................... ........................... M gm ngmiomz? ............................ Hmom _ 8 wEm .......................... 333 33$ E33 3?? M m? mag Zm?mmmw Zuammmm ZWSDmmmm 233% ............................. M m 4% xm HQ... -?, :4: 5%. .9; ........................... p a“ b Km .............................. a w é 0m mm m w Q SUBSTITUTE SHEET (RULE 26) 28/32 :5QO ©moi§ oimxéz 25%? qum a? 1%.: i?: 3Q! :31. am E. om {23 SENSE-Elm SA SNEWEM SUBSTITUTE SHEET (RULE 26) 2’3/32 wmm Emgwgw?mog EmanNNONQmOE 3%gw?mo?. ”Mawmga?éo é... -m- a? é; u «ac—«mm' Lnnnnnnnnmmmm .3 zoazgz seam came gear < gww > awmexx HOWM SUBSTITUTE SHEET (RULE 26) 22l32 3% 93% zo??z?mé ”Now?mog ”go?og Ema gm-.. a? mag 8.8 (I was ) Emma/x a0 SUBSTITUTE SHEET (RULE 26) 23/32 H|_|_|W am8.omo.“ zQENMEQQZE EN m?m THSEEM M308 NVBW SUBSTITUTE SHEET (RULE 26) 24f32 Ema; am3% 3mg away“, ”zm?mamw ”233%; ”gm?og 0 a é... -?- .$ $3 a Ea....-........~ SW8 Ei?é?TOA m WSGEAEGNE SUBSTITUTE SHEET (RULE 26) 251732 Egg 3% Egg Emma: ”233% ”magi Q m ”233%me a? 5%, $3. am: Inn n u a _uh_ mmm n E qu??mh E hmom 9 mEm TESS/Vi ENTVTEE WGGEAEGNE SUBSTITUTE SHEET (RULE 26)
NZ785232A 2017-03-02 Eribulin-based Antibody-Drug Conjugates and Methods of Use NZ785232B2 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US201662302562P 2016-03-02 2016-03-02
NZ744808A NZ744808B2 (en) 2017-03-02 Eribulin-based antibody-drug conjugates and methods of use

Publications (2)

Publication Number Publication Date
NZ785232A NZ785232A (en) 2025-05-30
NZ785232B2 true NZ785232B2 (en) 2025-09-02

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