IP Library › Granted Patent US 12,492,263
Granted Patent B2
US 12,492,263 · App. 17/720,717 · Granted Dec 9, 2025

Anti-HER2 antibodies and immunoconjugates

Inventors: Xiaocheng Chen (Burlingame, CA); Mark Dennis (San Carlos, CA); Jagath Reddy Junutula (Fremont, CA); Gail Lewis Phillips (San Carlos, CA); Thomas Harden Pillow (San Francisco, CA); Mark X. Sliwkowski (San Carlos, CA)
Assignee: Genentech, Inc.
C07K16/32A61K31/5517A61K31/675A61K31/704A61K39/3955A61K47/68A61K47/6809A61K47/6849A61K47/6855A61K47/6863A61K49/00C07K16/2863C07K16/3015G01N33/57415G01N33/57446G01N33/57492C07K2317/24C07K2317/34C07K2317/51C07K2317/515C07K2317/56C07K2317/565C07K2317/73C07K2317/92G01N2333/82
View Patent ↗
Loading inventors, assignments & file history…
Monitor This Case
Get email alerts when status or documents change.
Order Certified Copies
Most orders are placed with the USPTO same day — all within 24 business hours.
Order via The Patent Place →
Pre-filled with this patent's details
Quick Facts
Patent No.
US 12,492,263
App. No.
17/720,717
Granted
Dec 9, 2025
Kind
B2
Abstract

The invention provides anti-HER2 antibodies and immunoconjugates and methods of using the same.

Claims (21)

1 . An isolated antibody that binds to HER2, wherein the antibody comprises

(i)(a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 15; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 20 or 21; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 17; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 12; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 13; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 14;

(ii)(a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 15; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 22; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 12; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 13; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 14;

(iii) a light chain variable region comprising the sequence of SEQ ID NO: 10 and a heavy chain variable region comprising the sequence of SEQ ID NO: 11 with one of the following substitutions: (a) position 53 is serine, position 55 is serine, and position 101 is lysine; (b) position 53 is methionine and position 55 is serine; or (c) position 53 is leucine, wherein positions are numbered according to Kabat numbering; or

(iv) a light chain variable region comprising the sequence of SEQ ID NO: 10 and a heavy chain variable region comprising the sequence of SEQ ID NO: 11 with one of the following substitutions (a) HVR-H2 (SEQ ID NO: 16) is substituted with SEQ ID NO: 8 and HVR-H3 (SEQ ID NO: 17) is substituted with SEQ ID NO: 22; (b) HVR-H2 (SEQ ID NO: 16) is substituted with SEQ ID NO: 20; or (c) HVR-H2 (SEQ ID NO: 16) is substituted with SEQ ID NO: 21.

2 . The antibody of claim 1 , wherein the antibody comprises

(i) a light chain variable region comprising the sequence of SEQ ID NO: 10 and a heavy chain variable region comprising the sequence of SEQ ID NO: 11 with one of the following substitutions (a) position 53 is serine, position 55 is serine, and position 101 is lysine; (b); (b) position 53 is methionine and position 55 is serine; or (c) position 53 is leucine, wherein positions are numbered according to Kabat numbering; or

(ii) a light chain variable region comprising the sequence of SEQ ID NO: 10 and a heavy chain variable region comprising the sequence of SEQ ID NO: 11 with one of the following substitutions (a) HVR-H2 (SEQ ID NO: 16) is substituted with SEQ ID NO: 8 and HVR-H3 (SEQ ID NO: 17) is substituted with SEQ ID NO: 22; (b) HVR-H2 (SEQ ID NO: 16) is substituted with SEQ ID NO: 20; or (c) HVR-H2 (SEQ ID NO: 16) is substituted with SEQ ID NO: 21.

3 . The antibody of claim 1 , which is a monoclonal, humanized, or chimeric antibody.

4 . The antibody of claim 1 , which is an antibody fragment that binds HER2.

5 . The antibody of claim 1 , wherein the antibody binds to extracellular domain I of HER2.

6 . The antibody of claim 1 , which is an IgG1, IgG2a or IgG2b antibody.

7 . The antibody of claim 1 , wherein the antibody comprises at least one mutation in the heavy chain constant region selected from A118C and S400C.

8 . The antibody of claim 1 , wherein the antibody comprises at least one mutation in the light chain constant region selected from K149C and V205C.

9 . The antibody of claim 1 , wherein the antibody comprises the heavy chain constant region of SEQ ID NO: 28 or SEQ ID NO: 19.

10 . The antibody of claim 1 , wherein the antibody comprises the light chain constant region of SEQ ID NO: 25 or SEQ ID NO: 23.

11 . An isolated nucleic acid encoding the antibody of claim 1 .

12 . A host cell comprising the nucleic acid of claim 11 .

13 . A method of producing an antibody comprising culturing the host cell of claim 12 so that the antibody is produced.

14 . An immunoconjugate comprising the antibody of claim 1 and a cytotoxic agent.

15 . The antibody of claim 1 , conjugated to a label.

Continuity (6)
Continuation 16721525 · Dec 19, 2019
Division 16170819 · Oct 25, 2018
Division 15296454 · Oct 18, 2016
Division 14851001 · Sep 11, 2015
Provisional Application 62049594 · Sep 12, 2014
Related Publication 20230041134A1 · Feb 9, 2023
References Cited (144)
US 4427588A · Kaneko et al. · 1984 [cited by applicant]
US 5660856A · Adler-Moore et al. · 1997 [cited by applicant]
US 6660856B2 · Wang · 2003 [cited by applicant]
US 6949245B1 · Sliwkowski · 2005 [cited by applicant]
US 6984494B2 · Ralph · 2006 [cited by applicant]
US 7041292B1 · Sliwkowski · 2006 [cited by applicant]
US 7049311B1 · Thurston et al. · 2006 [cited by applicant]
US 7129254B2 · Berger et al. · 2006 [cited by applicant]
US 7265105B2 · Thurston et al. · 2007 [cited by applicant]
US 7449184B2 · Allison et al. · 2008 [cited by applicant]
US 7498298B2 · Doronina et al. · 2009 [cited by applicant]
US 7521541B2 · Eigenbrot et al. · 2009 [cited by applicant]
US 7855275B2 · Eigenbrot et al. · 2010 [cited by applicant]
US 7993834B2 · Mass · 2011 [cited by applicant]
US 8034808B2 · DeLavault et al. · 2011 [cited by applicant]
US 8309300B2 · Junutula et al. · 2012 [cited by applicant]
US 8372396B2 · Andya et al. · 2013 [cited by applicant]
US 8481042B2 · Commercon et al. · 2013 [cited by applicant]
US 8487092B2 · Howard et al. · 2013 [cited by applicant]
US 8592576B2 · Howard et al. · 2013 [cited by applicant]
US 8691232B2 · Derynck et al. · 2014 [cited by applicant]
US 8765740B2 · Li et al. · 2014 [cited by applicant]
US 8802667B2 · Li et al. · 2014 [cited by applicant]
US 8809320B2 · Li et al. · 2014 [cited by applicant]
US 9000130B2 · Bhakta et al. · 2015 [cited by applicant]
US 9518118B2 · Chen · 2016 [cited by examiner]
US 10179820B2 · Chen · 2019 [cited by examiner]
US 10314846B2 · Chen · 2019 [cited by examiner]
US 10556966B2 · Chen · 2020 [cited by examiner]
US 20020141993A1 · Ashkenazi et al. · 2002 [cited by applicant]
US 20050208043A1 · Adams et al. · 2005 [cited by applicant]
US 20050244417A1 · Ashkenazi et al. · 2005 [cited by applicant]
US 20070092940A1 · Eigenbrot et al. · 2007 [cited by applicant]
US 20080112957A1 · Fendly et al. · 2008 [cited by applicant]
US 20090175865A1 · Eigenbrot et al. · 2009 [cited by applicant]
US 20100003766A1 · Eigenbrot et al. · 2010 [cited by applicant]
US 20100111856A1 · Gill et al. · 2010 [cited by applicant]
US 20110033460A1 · Fendly et al. · 2011 [cited by applicant]
US 20110137017A1 · Eigenbrot et al. · 2011 [cited by applicant]
US 20110256157A1 · Howard et al. · 2011 [cited by applicant]
US 20110301334A1 · Bhakta et al. · 2011 [cited by applicant]
US 20130028917A1 · Howard et al. · 2013 [cited by applicant]
US 20130195845A1 · Fendly et al. · 2013 [cited by applicant]
US 20130266595A1 · Flygare et al. · 2013 [cited by applicant]
US 20140111298A1 · Chiang et al. · 2014 [cited by applicant]
US 20140120118A1 · Howard · 2014 [cited by applicant]
US 20140288280A1 · Bhakta et al. · 2014 [cited by applicant]
US 20150017094A1 · Gill et al. · 2015 [cited by applicant]
US 20150017188A1 · Eigenbrot, Jr. et al. · 2015 [cited by applicant]
US 20150111298A1 · Lattemann et al. · 2015 [cited by applicant]
US 20150209444A1 · Chari et al. · 2015 [cited by applicant]
US 20150344482A1 · Howard · 2015 [cited by applicant]
US 20160074527A1 · Flygare et al. · 2016 [cited by applicant]
US 20160096893A1 · Chen et al. · 2016 [cited by applicant]
US 20160130358A1 · Bhakta et al. · 2016 [cited by applicant]
US 20160310611A1 · Flygare et al. · 2016 [cited by applicant]
US 20170095570A1 · Dragovich et al. · 2017 [cited by applicant]
US 20170274092A1 · Chen et al. · 2017 [cited by applicant]
US 20180185486A1 · Dragovich et al. · 2018 [cited by applicant]
CN 101023100 · 2007 [cited by applicant]
EP 1413582B1 · 2006 [cited by applicant]
EP 2540745A1 · 2013 [cited by applicant]
WO WO199817797A1 · 1998 [cited by applicant]
WO WO2000012507A2 · 2000 [cited by applicant]
WO WO2004087717A1 · 2004 [cited by applicant]
WO WO2005023814A1 · 2005 [cited by applicant]
WO WO2005085251A1 · 2005 [cited by applicant]
WO WO2006034488A2 · 2006 [cited by applicant]
WO WO2006033700A2 · 2006 [cited by applicant]
WO WO2007085930A1 · 2007 [cited by applicant]
WO WO2010043877A1 · 2010 [cited by applicant]
WO WO2010091150A1 · 2010 [cited by applicant]
WO WO2011056983A1 · 2011 [cited by applicant]
WO WO2011130598A1 · 2011 [cited by applicant]
WO WO2011130613A1 · 2011 [cited by applicant]
WO WO2011130616A1 · 2011 [cited by applicant]
WO WO2011156328A1 · 2011 [cited by applicant]
WO WO2012014147A1 · 2012 [cited by applicant]
WO WO2012112708A1 · 2012 [cited by applicant]
WO WO2013041606A1 · 2013 [cited by applicant]
WO WO2013053873A1 · 2013 [cited by applicant]
WO WO2013055987A1 · 2013 [cited by applicant]
WO WO2013055990A1 · 2013 [cited by applicant]
WO WO2013055993A1 · 2013 [cited by applicant]
WO WO2013177481A1 · 2013 [cited by applicant]
WO WO2014011518A1 · 2014 [cited by applicant]
WO WO2014057072A1 · 2014 [cited by applicant]
WO WO2014057113A1 · 2014 [cited by applicant]
WO WO2014057114A1 · 2014 [cited by applicant]
WO WO2014057115A1 · 2014 [cited by applicant]
WO WO2014057117A1 · 2014 [cited by applicant]
WO WO2014057118A1 · 2014 [cited by applicant]
WO WO2014057119A1 · 2014 [cited by applicant]
WO WO2014057120A1 · 2014 [cited by applicant]
WO WO2014057122A1 · 2014 [cited by applicant]
WO WO2014096365A1 · 2014 [cited by applicant]
WO WO2014096368A1 · 2014 [cited by applicant]
WO WO2014130879A2 · 2014 [cited by applicant]
WO WO2015095124A1 · 2015 [cited by applicant]
WO WO2016040723A1 · 2016 [cited by applicant]
WO WO2016040856A2 · 2016 [cited by applicant]
WO WO2016044396A1 · 2016 [cited by applicant]
WO WO2016044560A1 · 2016 [cited by applicant]
Antonow et al., “Synthesis of a novel C2-aryl pyrrolo[2,1-c][1,4]benzodiazepine-5, 11-dione library: effect of C2-aryl substitution on cytotoxicity and non-covalent DNA binding” Bioorg Med Chem. 15(8):3041-53 (Apr. 15, … [cited by applicant]
Antonow et al., “Synthesis of DNA-interactive pyrrolo[2,1-c][1,4]benzodiazepines (PBDs)” Chem Rev. 111(4):2815-64 ( 2011). [cited by applicant]
Arima et al., “Studies on tomaymycin, a new antibiotic. I. Isolation and properties of tomaymycin” J Antibiot (Tokyo) 25(8):437-44 (Aug. 1972). [cited by applicant]
Baselga et al., “Recombinant Humanized Anti-HER2 Antibody (Herceptin ™) Enhances the Antitumor Activity of Paclitaxel and Doxorubicin against HER2/neu Overexpressing Human Breast Cancer Xenografts” Cancer Res. 58:2825-2… [cited by applicant]
Bookman et al., “Evaluation of Monoclonal Humanized Anti-HER2 Antibody, Trastuzumab, in Patients with Recurrent or Refractory Ovarian or Primary Peritoneal Carcinoma With Overexpression of HER2: A Phase II Trial of the … [cited by applicant]
Bose et al., “New approaches to pyrrolo[2,1-c][1,4]benzodiazepines: synthesis, DNA-binding and cytotoxicity of DC-81” Tetrahedron 48(4):751-8 ( 1992). [cited by applicant]
Fendly et al., “Characterization of murine monoclonal antibodies reactive to either the human epidermal growth factor receptor or HER2/neu gene product” Cancer Res 50:1550-1558 (Mar. 1, 1990). [cited by applicant]
Gregson et al., “Linker Length Modulates DNA Cross-Linking Reactivity and Cytotoxic Potency of C8/C8′ Ether-Linked C2-exo-Unsaturated Pyrrolo[2,1-c][1,4]benzodiazepine (PBD) Dimers” J. Med. Chem. 47(5):1161-74 ( 2004). [cited by applicant]
Gregson, et al., “Design, Synthesis, and Evaluation of a Novel Pyrrolobenzodiazepine DNA-Interactive Agent with Highly Efficient Cross-Linking Ability and Potent Cytotoxicity”, J Med Chem 44, 737-748 (2001). [cited by applicant]
Gregson, et al., “Synthesis of a novel C2/C2′-exo unsaturated pyrrolobenzodiazepine cross-linking agent with remarkable DNA binding affinity and cytotoxicity”, Chem Commun, 797-798 (1999). [cited by applicant]
Grimm et al., “Reaction Safety: An Improved Procedure for the Preparation of 1,3,4,12a-Tetrahydro-11H-[1,4]-oxanio[3,4-c][1,4]benzodiazepine-6,12-dione with Iron in Acetic Acid” Organic Process Research And Development … [cited by applicant]
Hara et al., “DC 102, a new glycosidic pyrrolo(1,4)benzodiazepine antibiotic produced by [cited by applicant]
Hochlowski et al., “Abbeymycin, a new anthramycin-type antibiotic produced by a streptomycete” J Antibiot (Tokyo) 40(2):145-8 (Feb. 1987). [cited by applicant]
Howard et al., “Synthesis of a novel C2/C2′-aryl-substituted pyrrolo[2,1-c][1,4]benzodiazepine dimer prodrug with improved water solubility and reduced DNA reaction rate” Bioorg Med Chem Lett 19(22):6463-6466 ( 2009). [cited by applicant]
Hurley et al., “Covalent Binding of Antitumor Antibiotics in the Minor Groove of DNA. Mechanism of Action of CC-1065 and the Pyrrolo(1,4)benzodiazepines” Acc Chem Res 19:230-237 ( 1986). [cited by applicant]
International Search Report and Written Opinion for PCT Application PCT/US2015/049549, filed Sep. 11, 2015, pp. 14 (mailed Dec. 16, 2015). [cited by applicant]
ISR and Written Opinion for PCT/EP2013/077705 (10 pages). [cited by applicant]
ISR and Written Opinion for PCT/US2013/042566 (11 pages). [cited by applicant]
ISR and Written Opinion for PCT/US2015/049549 (12 pages). [cited by applicant]
ISR and Written Opinion for PCT/US2016/054858 (13 pages). [cited by applicant]
Itoh et al., “Sibanomicin, a new pyrrolo[1,4]benzodiazepine antitumor antibiotic produced by a [cited by applicant]
Kamal et al., “Design, synthesis, and evaluation of mixed imine-amine pyrrolobenzodiazepine dimers with efficient DNA binding affinity and potent cytotoxicity” Bioorg Med Chem. 12(20):5427-36 (2004). [cited by applicant]
Kamal et al., “Design, synthesis, and evaluation of new noncross-linking pyrrolobenzodiazepine dimers with efficient DNA binding ability and potent antitumor activity” J Med Chem. 45(21):4679-88 (2002). [cited by applicant]
Kamal et al., “Pyrrolo[2,1-c][1,4]benzodiazepine-beta-glucuronide prodrugs with a potential for selective therapy of solid tumors by PMT and ADEPT strategies” Bioorg Med Chem Lett. 18(13):3769-73 (Jul. 1, 2008). [cited by applicant]
Kaneko, et al., “A new and mild method for the reduction of secondary amides to carbinolamine ethers and imines: a conversion of oxotomaymycin to tomaymycin”, Tetrahedron Letters 24(47), 5165-5168 (1983). [cited by applicant]
Kaneko, et al., “Bicyclic and tricyclic analogues of anthramycin”, Journal of Medicinal Chemistry 28(3), 388-392 (1985). [cited by applicant]
Kang, et al. “Synthesis of a novel C2-aryl substituted 1,2-unsaturated pyrrolobenzodiazepine”, Chemical Communications 14, 1688-1698 (2003). [cited by applicant]
Kohn, Mechanism of Action of Antimicrobial and Antitumor Agents “Anthramycin” New York:Springer-Verlag,:3-11 (1975). [cited by applicant]
Konishi et al., “Chicamycin, a new antitumor antibiotic. II. Structure determination of chicamycins A and B” J Antibiot (Tokyo) 37(3):200-6 (Mar. 1984). [cited by applicant]
Kunimoto et al., “Mazethramycin, a new member of anthramycin group antibiotics” J. Antibiotics 33(6):665-7 (Jun. 1980). [cited by applicant]
Langley et al., “A versatile and efficient synthesis of carbinolamine-containing pyrrolo[1,4]benzodiazepines via the cyclization of N-(2-aminobenzoyl)pyrrolidine-2-carboxaldehyde diethyl thioacetals: total synthesis of … [cited by applicant]
Leber et al., “A revised structure of sibiromycin” J. Am. Chem. Soc. 110:2992-93 ( 1988). [cited by applicant]
Leimgruber et al., “Isolation and characterization of anthramycin, a new antitumor antibiotic” J Am Chem Soc 87(24):5791-5793 (1965). [cited by applicant]
Leimgruber et al., “The structure of anthramycin” J Am Chem Soc 87(24):5793-5795 (1965). [cited by applicant]
Martin et al., “Sequence-selective interaction of the minor-groove interstrand cross-linking agent SJG-136 with naked and cellular DNA: footprinting and enzyme inhibition studies” Biochemistry 44(11):4135-47 (Mar. 22, 2… [cited by applicant]
Scheer JM et al., “Reorienting the Fab Domains of Trastuzumab Results in Potent HER2 Activators,” PLoS One, vol. 7, No. 12, e51817, 13 pages (2012). [cited by applicant]
Shimizu et al., “Prothracarcin, a novel antitumor antibiotic” J. Antibiotics 8:972-8 (Aug. 1982). [cited by applicant]
Takeuchi et al., “Neothramycins A and B, new antitumor antibiotics” J Antibiot (Tokyo) 29(1):93-6 (1976). [cited by applicant]
Thurston et al., “Synthesis of DNA-Interactive Pyrrolo[2,1-c][1,4]benzodiazepines” Chem Rev 94:433-465 ( 1994). [cited by applicant]
Thurston et al., “The molecular recognition of DNA” Chem. Brit. 26(8):767-72 (Aug. 1990). [cited by applicant]
Tsunakawa et al., “Porothramycin, a new antibiotic of the anthramycin group: production, isolation, structure and biological activity” J Antibiot (Tokyo) 41(10):1366-73 (Oct. 1988). [cited by applicant]