IP Library › Granted Patent US 12,509,524
Granted Patent B2
US 12,509,524 · App. 17/280,239 · Granted Dec 30, 2025

Antigen-binding molecule comprising altered antibody variable region

Inventors: Tomoyuki Igawa (Singapore, SG); Shu Feng (Singapore, SG); Shu Wen Samantha Ho (Singapore, SG); Hirotake Shiraiwa (Shizuoka, JP)
Assignee: Chugai Seiyaku Kabushiki Kaisha
C07K16/2878C07K16/2809C07K16/303C07K2317/31C07K2317/522C07K2317/53C07K2317/55C07K2317/71C07K2317/73C07K2317/92
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 12,509,524
App. No.
17/280,239
Granted
Dec 30, 2025
Kind
B2
Abstract

An antigen-binding molecule capable of binding to multiple different antigens (e.g., CD3 on T cells, and CD137 on T cells, NK cells, DC cells, and/or the like), but does not nonspecifically crosslink two or more immune cells such as T cells is provided. Such multispecific antigen-binding molecule is capable of modulating and/or activating an immune response while circumventing the cross-linking between different cells (e.g., different T cells) resulting from the binding of a conventional multispecific antigen-binding molecule to antigens expressed on the different cells, which is considered to be responsible for adverse reactions when the multispecific antigen-binding molecule is used as a drug.

Claims (73)

1 . An antigen-binding molecule comprising:

(i) a first antigen-binding domain comprising a first heavy chain variable (VH) region, a first heavy chain constant (CH1) region, a first light chain variable (VL) region, and a first light chain constant (CL) region; and

(ii) a second antigen-binding domain comprising a second VH region, a second CH1 region, a second VL region, and a second CL region; and

(iii) a third antigen-binding domain comprising a third VH region and a third VL region, wherein the antigen-binding molecule further comprises one or more of the following;

at least one bond between an amino acid residue in the first CH1 region and an amino acid residue in the second CH1 region,

at least one bond between an amino acid residue in the first CL region and an amino acid residue in the second CL region,

at least one bond between an amino acid residue in the first CH1 region and an amino acid residue in the second CL region, and

at least one bond between an amino acid residue in the first CL region and an amino acid residue in the second CH1 region;

wherein the first antigen-binding domain is linked to the second antigen-binding domain via an Fc region, a disulfide bond, or a linker,

wherein the first antigen-binding domain binds to a first antigen and to a second antigen different from the first antigen, but does not bind to both the first and second antigens at the same time when the first and second antigens are expressed on cell membranes of separate cells,

wherein the third antigen-binding domain binds to a third antigen that is different from the first and second antigens;

wherein the third antigen-binding domain is linked to one of the following: the first antigen-binding domain, the second antigen-binding domain, or an Fc region; and

wherein either (a) or (b) is true;

(a) the second antigen-binding domain binds to the first antigen and to the second antigen, but does not bind to both the first and second antigens at the same time when the first and second antigens are expressed on cell membranes of different cells; or

(b) the second antigen-binding domain binds to either the first antigen or the second antigen, and not to the other.

2 . The antigen-binding molecule of claim 1 , wherein one or both of the first antigen-binding domain and the second antigen binding domain have an alteration, compared to the VH region sequence of SEQ ID NO: 184 and the VL region sequence of SEQ ID NO: 185, of at least one amino acid at a position or positions selected from Kabat numbering positions 31 to 35, 50 to 65, 71 to 74, and 95 to 102 of SEQ ID NO: 184, and Kabat numbering positions 24 to 34, 50 to 56, and 89 to 97 of SEQ ID NO: 185.

3 . The antigen-binding molecule of claim 1 , wherein the first antigen-binding domain and the second antigen-binding domain are linked via an Fc region.

4 . The antigen-binding molecule of claim 3 , wherein the Fc region has reduced binding activity against human Fc gamma R as compared with that of the Fc region of a wild-type human IgG1 antibody.

5 . The antigen-binding molecule of claim 1 , wherein the third antigen-binding domain is linked to either the first antigen-binding domain or the second antigen-binding domain through one of the following linkages:

(A) a link between the C-terminus of a polypeptide comprising the third VH region and the N-terminus of a polypeptide comprising the first or second VH region,

(B) a link between the C-terminus of a polypeptide comprising the third VH region and the N-terminus of a polypeptide comprising the first or second VL region,

(C) a link between the C-terminus of a polypeptide comprising the third VL region and the N-terminus of a polypeptide comprising the first or second VH region, or

(D) a link between the C-terminus of a polypeptide comprising the third VL region and the N-terminus of a polypeptide comprising the first or second VL region.

6 . The antigen-binding molecule of claim 1 ,

wherein the at least one bond is a disulfide bond,

wherein the first antigen-binding domain comprises a heavy chain hinge region,

wherein the second antigen-binding domain comprises a heavy chain hinge region, and

wherein the first antigen-binding domain and the second antigen-binding domain are linked to each other by one or more native disulfide bonds between their respective hinge regions.

7 . The antigen-binding molecule of claim 1 ,

wherein the amino acid residue at EU numbering position 191 in the first CH1 region forms a bond with the amino acid residue at EU numbering position 191 in the second CH1 region.

8 . The antigen-binding molecule of claim 1 , wherein the first antigen is a molecule specifically expressed on a T cell.

9 . The antigen-binding molecule of claim 8 , wherein the second antigen is a molecule expressed on a T cell or any other immune cell.

10 . The antigen-binding molecule of claim 1 , wherein the first antigen is human CD3 and the second antigen is human CD137.

11 . The antigen-binding molecule of claim 1 , wherein the third antigen is a molecule specifically expressed in a cancer cell.

12 . The antigen-binding molecule of claim 10 , wherein the third antigen is a molecule specifically expressed in a cancer cell.

13 . A method for producing an antigen-binding molecule, the method comprising:

(a) providing a host cell containing one or more nucleic acids encoding one or more polypeptides that together form:

(1) a first antigen-binding domain comprising a first VH region, a first CH1 region, a first VL region, and a first CL region;

(2) a second antigen-binding domain comprising a second VH region, a second CH1 region, a second VL region, and a second CL region; and

(3) a third antigen-binding domain comprising a third VH region and a third VL region,

wherein:

(i) each of the first and second antigen-binding domains binds to both a first antigen and a second antigen that is different from the first antigen, but does not bind to both the first and second antigens at the same time when the first and second antigens are expressed on cell membranes of separate cells, or

(ii) the first antigen-binding domain binds to a first antigen and a second antigen that is different from the first antigen, but does not bind to both the first and second antigens at the same time when the first and second antigens are expressed on cell membranes of separate cells, and the second antigen-binding domain binds only to either the first antigen or the second antigen and not to the other;

wherein the third antigen-binding domain binds to a third antigen different from the first and second antigens;

(b) culturing the host cell so that the antigen-binding molecule comprising the one or more polypeptides of (a) is produced,

wherein the first antigen-binding domain and the second antigen-binding domain of the produced antigen-binding molecule are linked via a first linkage and a second linkage,

wherein the first linkage is via an Fc region, a disulfide bond or a linker, and

wherein the second linkage is selected from:

at least one bond between an amino acid residue in the first CH1 region and an amino acid residue in the second CH1 region,

at least one bond between an amino acid residue in the first CL region and an amino acid residue in the second CL region,

at least one bond between an amino acid residue in the first CH1 region and an amino acid residue in the second CL region, or

at least one bond between an amino acid residue in the first CL region and an amino acid residue in the second CH1 region; and

optionally, wherein the third antigen-binding domain is linked to any one of the first antigen-binding domain and the second antigen-binding domain, or an Fc region; and

(c) obtaining the antigen-binding molecule produced in (b).

14 . The method of claim 13 , further comprising preparing the host cell of (a) by a method comprising:

(1) identifying a starting antigen-binding domain that has a VH region of SEQ ID NO: 184 and a VL region of SEQ ID NO: 185;

(2) preparing a library of antigen-binding domains that vary from the starting antigen-binding domain and from each other at one or more positions selected from Kabat numbering positions 31 to 35, 50 to 65, 71 to 74, and 95 to 102 in SEQ ID NO: 184 and Kabat numbering positions 24 to 34, 50 to 56, and 89 to 97 in SEQ ID NO: 185;

(3) selecting, from the prepared library, an antigen-binding domain comprising a VH region and a VL region that together bind the first antigen and the second antigen, but do not bind to the first antigen and the second antigen at the same time when the first and second antigens are expressed on cell membranes of separate cells;

(4) preparing one or more nucleic acids encoding one or more polypeptides that together comprise the selected antigen-binding domain; and

(5) introducing the one or more nucleic acids of (4) into a host cell, thereby preparing the host cell of (a).

15 . The method of claim 13 , wherein;

the at least one bond of the second linkage is a disulfide bond,

the first antigen-binding domain comprises a heavy chain hinge region,

the second antigen-binding domain comprises a heavy chain hinge region, and

the first linkage links the first antigen-binding domain to the second antigen-binding domain by one or more native disulfide bonds in the respective hinge regions.

16 . A method of treating cancer, the method comprising administering the antigen-binding molecule of claim 12 to a subject in need of treatment for cancer.

17 . The antigen-binding molecule of claim 1 , wherein the at least one bond is a disulfide bond.

18 . The antigen-binding molecule of claim 1 , wherein one or both of the first antigen-binding domain and the second antigen-binding domain comprise the amino acid sequence of the VH region of SEQ ID NO: 184 with at least one amino acid alteration or the amino acid sequence of the VL region of SEQ ID NO: 185 with at least one amino acid alteration, wherein the alteration is a substitution or an insertion.

19 . The antigen-binding molecule of claim 1 , wherein the amino acid residue in the first or second CH1 region is at a CH1 position selected from EU numbering positions 119, 122, 123, 131, 132, 133, 134, 135, 136, 137, 139, 140, 148, 150, 155, 156, 157, 159, 160, 161, 162, 163, 165, 167, 174, 176, 177, 178, 190, 191, 192, 194, 195, 197, 213, and 214.

20 . The antigen-binding molecule of claim 1 , wherein the amino acid residue in the first or second CL region is at a CL position selected from EU numbering positions 109, 112, 121, 126, 128, 151, 152, 153, 156, 184, 186, 188, 190, 200, 201, 202, 203, 208, 210, 211, 212, and 213.

21 . The method of claim 13 , further comprising:

preparing a library of polypeptides comprising a plurality of antigen-binding domains, each of which comprises a VH region and a VL region, wherein the members of the library differ from each other by one or more amino acid substitutions or insertions, or both, in their respective VH regions or in their respective VL regions, or in both; and

selecting, from the prepared library, an antigen-binding domain that binds to both the first antigen and the second antigen, but does not bind to the first antigen and the second antigen at the same time.

Assignments (3)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jul 13, 2021
From: IGAWA, TOMOYUKI; SHIRAIWA, HIROTAKE
To: CHUGAI SEIYAKU KABUSHIKI KAISHA
Reel/Frame 056834/0287 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jul 13, 2021
From: FENG, SHU; HO, SHU WEN SAMANTHA
To: CHUGAI PHARMABODY RESEARCH PTE. LTD.
Reel/Frame 056834/0372 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jul 13, 2021
From: CHUGAI PHARMABODY RESEARCH PTE. LTD.
To: CHUGAI SEIYAKU KABUSHIKI KAISHA
Reel/Frame 056834/0438 →
Priority Claims (1)
JP 2018-185120 · Sep 28, 2018 · national
Continuity (1)
Related Publication 20220112296A1 · Apr 14, 2022
References Cited (330)
US 6344443B1 · Liu et al. · 2002 [cited by applicant]
US 9334331B2 · Igawa · 2016 [cited by examiner]
US 11154615B2 · Igawa et al. · 2021 [cited by applicant]
US 11274151B2 · Naoi et al. · 2022 [cited by applicant]
US 11718672B2 · Naoi et al. · 2023 [cited by applicant]
US 11739149B2 · Igawa et al. · 2023 [cited by applicant]
US 11952422B2 · Shimizu et al. · 2024 [cited by applicant]
US 20060121042A1 · Dallaqua et al. · 2006 [cited by applicant]
US 20070071675A1 · Wu et al. · 2007 [cited by applicant]
US 20070237767A1 · Lazar et al. · 2007 [cited by applicant]
US 20070286859A1 · Lazar et al. · 2007 [cited by applicant]
US 20080014205A1 · Horowitz et al. · 2008 [cited by applicant]
US 20100150918A1 · Kufer et al. · 2010 [cited by applicant]
US 20100322946A1 · Bostrom et al. · 2010 [cited by applicant]
US 20120328624A1 · Yoshida et al. · 2012 [cited by applicant]
US 20130129723A1 · Blankenship et al. · 2013 [cited by applicant]
US 20140112914A1 · Nezu et al. · 2014 [cited by applicant]
US 20140242077A1 · Choi et al. · 2014 [cited by applicant]
US 20140341906A1 · Taylor et al. · 2014 [cited by applicant]
US 20150166636A1 · Igawa et al. · 2015 [cited by applicant]
US 20160264960A1 · Ishii et al. · 2016 [cited by applicant]
US 20160280787A1 · Igawa et al. · 2016 [cited by applicant]
US 20170037130A1 · Raum et al. · 2017 [cited by applicant]
US 20170274072A1 · Kumagai et al. · 2017 [cited by applicant]
US 20170306036A1 · Vu et al. · 2017 [cited by applicant]
US 20180201691A1 · Hudson · 2018 [cited by applicant]
US 20180296668A1 · Igawa et al. · 2018 [cited by applicant]
US 20190119406A1 · Zhang · 2019 [cited by applicant]
US 20200332001A1 · Igawa et al. · 2020 [cited by applicant]
US 20200377595A1 · Shimizu et al. · 2020 [cited by applicant]
US 20210301016A1 · Naoi et al. · 2021 [cited by applicant]
US 20210388087A1 · Ho et al. · 2021 [cited by applicant]
US 20220040297A1 · Igawa et al. · 2022 [cited by applicant]
US 20220251201A1 · Naoi et al. · 2022 [cited by applicant]
US 20230121511A1 · Chichili et al. · 2023 [cited by applicant]
US 20240010725A1 · Naoi et al. · 2024 [cited by applicant]
US 20240026000A1 · Igawa et al. · 2024 [cited by applicant]
US 20240270846A1 · Shimizu et al. · 2024 [cited by applicant]
CN 1069124 · 1993 [cited by applicant]
CN 101123983 · 2008 [cited by applicant]
EP 1293514A · 2003 [cited by applicant]
EP 1752471A · 2007 [cited by applicant]
EP 2647707A · 2013 [cited by applicant]
EP 2731970A · 2014 [cited by applicant]
EP 3070168A · 2016 [cited by applicant]
EP 3130606A · 2017 [cited by applicant]
EP 3219724A · 2017 [cited by applicant]
EP 3305322A · 2018 [cited by applicant]
EP 3227332B1 · 2019 [cited by examiner]
EP 3831854A · 2021 [cited by applicant]
JP 2007536912 · 2007 [cited by applicant]
JP 2008518023 · 2008 [cited by applicant]
JP 2008526809 · 2008 [cited by applicant]
JP 2010524851 · 2010 [cited by applicant]
JP 2012501648 · 2012 [cited by applicant]
JP 2021508441A · 2021 [cited by applicant]
JP 2021159081A · 2021 [cited by applicant]
RU 2010129549A · 2012 [cited by applicant]
RU 2014109551 · 2015 [cited by applicant]
RU 2016143383 · 2018 [cited by applicant]
WO WO9219973 · 1992 [cited by applicant]
WO WO9418221 · 1994 [cited by applicant]
WO WO9514714 · 1995 [cited by applicant]
WO WO0042072 · 2000 [cited by applicant]
WO WO0177342 · 2001 [cited by applicant]
WO WO2005070966 · 2005 [cited by applicant]
WO WO2006019447 · 2006 [cited by applicant]
WO WO2006047340 · 2006 [cited by applicant]
WO WO2006047639 · 2006 [cited by applicant]
WO WO2006072620 · 2006 [cited by applicant]
WO WO2006083706 · 2006 [cited by applicant]
WO WO2008119567 · 2008 [cited by applicant]
WO WO2008157379 · 2008 [cited by applicant]
WO WO2009025846 · 2009 [cited by applicant]
WO WO2009080252A1 · 2009 [cited by applicant]
WO WO2010027981 · 2010 [cited by applicant]
WO WO2010035012 · 2010 [cited by applicant]
WO WO2010080538 · 2010 [cited by applicant]
WO WO2011093097 · 2011 [cited by applicant]
WO WO2011133886 · 2011 [cited by applicant]
WO WO2012064792 · 2012 [cited by applicant]
WO WO2012064792A2 · 2012 [cited by examiner]
WO WO2012073985 · 2012 [cited by applicant]
WO WO2012096994 · 2012 [cited by applicant]
WO WO2012143524 · 2012 [cited by applicant]
WO WO2012162067 · 2012 [cited by applicant]
WO WO2012162068A2 · 2012 [cited by applicant]
WO WO2013026833 · 2013 [cited by applicant]
WO WO2013026839 · 2013 [cited by applicant]
WO WO2013055958 · 2013 [cited by applicant]
WO WO2013059593 · 2013 [cited by applicant]
WO WO2013093809 · 2013 [cited by applicant]
WO WO2013126746 · 2013 [cited by applicant]
WO WO2013180200 · 2013 [cited by applicant]
WO WO2013187495 · 2013 [cited by applicant]
WO WO2014116846 · 2014 [cited by applicant]
WO WO2015068847 · 2015 [cited by applicant]
WO WO2015138615 · 2015 [cited by applicant]
WO WO2015156268 · 2015 [cited by applicant]
WO WO2016040856 · 2016 [cited by applicant]
WO WO2016076345 · 2016 [cited by applicant]
WO WO2016122702A1 · 2016 [cited by applicant]
WO WO2016194992A1 · 2016 [cited by examiner]
WO WO2017021349 · 2017 [cited by applicant]
WO WO2017070608A1 · 2017 [cited by examiner]
WO WO2017096361A1 · 2017 [cited by applicant]
WO WO2017191101 · 2017 [cited by applicant]
WO WO2018027204 · 2018 [cited by applicant]
WO WO2018114748 · 2018 [cited by applicant]
WO WO2018114754 · 2018 [cited by applicant]
WO WO2018162517A1 · 2018 [cited by examiner]
WO WO2018232088 · 2018 [cited by applicant]
WO WO2019111871 · 2019 [cited by applicant]
WO WO2019131988 · 2019 [cited by applicant]
WO WO2019234220A1 · 2019 [cited by applicant]
WO WO2020027330 · 2020 [cited by applicant]
WO WO2020067399 · 2020 [cited by applicant]
WO WO2020067419 · 2020 [cited by applicant]
WO WO2020076977A2 · 2020 [cited by applicant]
WO WO2021157679 · 2021 [cited by applicant]
WO WO2021200898 · 2021 [cited by applicant]
WO WO2021201087 · 2021 [cited by applicant]
WO WO2023054423A1 · 2023 [cited by applicant]
Janeway CA Jr, Travers P, Walport M, et al. Immunobiology: The Immune System in Health and Disease. 5th edition. New York: Garland Science; 2001. The interaction of the antibody molecule with specific antigen. Available… [cited by examiner]
Chiu et al. Antibody Structure and Function: The Basis for Engineering Therapeutics. Antibodies (Basel). Dec. 3, 2019;8(4):55. doi: 10.3390/antib8040055 (Year: 2019). [cited by examiner]
Clark et al. Influence of canonical structure determining residues on antibody affinity and stability. J Struct Biol. Feb. 2014;185(2):223-7. doi: 10.1016/j.jsb.2013.08.009 (Year: 2013). [cited by examiner]
Hummer AM, Abanades B, Deane CM. Advances in computational structure-based antibody design. Curr Opin Struct Biol. Jun. 2022;74:102379. doi: 10.1016/j.sbi.2022.102379. Epub Apr. 28, 2022. PMID: 35490649. (Year: 2022). [cited by examiner]
Shang et al. (Characterization of the native and denatured Herceptin by enzyme linked immunosorbent assay and quartz crystal microbalance using a high-affinity single chain fragment variable recombinant antibody. Anal C… [cited by examiner]
Bostrom et al. (Variants of the antibody Herceptin that interact with HER2 and VEGF at the antigen binding site. Science. Mar. 20, 2009;323(5921):1610-4. doi: 10.1126/science.1165480 (Year: 2009). [cited by examiner]
Bostrom et al. (Variants of the antibody Herceptin that interact with HER2 and VEGF at the antigen binding site. Science. Mar. 20, 2009;323(5921):1610-4. doi: 10.1126/science.1165480 Supplementary. (Year: 2009). [cited by examiner]
Escobar-Cabrera E, Lario P, Baardsnes J, Schrag J, Durocher Y, Dixit S. Asymmetric Fc Engineering for Bispecific Antibodies with Reduced Effector Function. Antibodies (Basel). May 16, 2017;6(2):7. doi: 10.3390/antib6020… [cited by examiner]
Schlothauer et al. (Novel human IgG1 and IgG4 Fc-engineered antibodies with completely abolished immune effector functions. Protein Eng Des Sel. Oct. 2016;29(10):457-466. doi: 10.1093/protein/gzw040 (Year: 2016). [cited by examiner]
Somasundaram C, Sundarapandiyan K, Keler T, Deo YM, Graziano RF. Development of a trispecific antibody conjugate that directs two distinct tumor-associated antigens to CD64 on myeloid effector cells. Hum Antibodies. 199… [cited by examiner]
U.S. Appl. No. 15/035,098, Igawa et al., filed May 6, 2016 (abandoned). [cited by applicant]
U.S. Appl. No. 16/704,464, Igawa et al., filed Dec. 5, 2019. [cited by applicant]
U.S. Appl. No. 15/525,603, Igawa et al., filed May 10, 2017. [cited by applicant]
U.S. Appl. No. 16/769,299, Shimizu et al., filed Jun. 3, 2020. [cited by applicant]
U.S. Appl. No. 17/272,972, Ho et al., filed Mar. 3, 2021. [cited by applicant]
U.S. Appl. No. 17/216,981, Naoi et al., filed Mar. 30, 2021. [cited by applicant]
U.S. Appl. No. 17/264,388, Shiraiwa et al., filed Jan. 29, 2021. [cited by applicant]
U.S. Appl. No. 17/264,388, filed Jan. 29, 2021, Shiraiwa et al. [cited by applicant]
U.S. Appl. No. 17/272,972, filed Mar. 3, 2021, Ho et al. [cited by applicant]
Ashkenazi, “Directing cancer cells to self-destruct with pro-apoptotic receptor agonists,” Nat Rev Drug Discov, Dec. 2008, 7(12):1001-1012. [cited by applicant]
Brinkmann et al., “The making of bispecific antibodies,” mAbs, Feb./Mar. 2017, 9(2):182-212. [cited by applicant]
Carter et al., “Next generation antibody drugs: pursuit of the ‘high-hanging fruit’,” Nat Rev Drug Discov, Mar. 2018, 17(3):197-223. doi: 10.1038/nrd.2017.227. [cited by applicant]
Chan et al., “Therapeutic antibodies for autoimmunity and inflammation,” Nat Rev Immunol, May 2010, 10(5):301-316. doi: 10.1038/nri2761. [cited by applicant]
Clackson et al., “Making antibody fragments using phage display libraries,” Nature, Aug. 15, 1991, 352(6336):624-628. [cited by applicant]
Clark, “IgG effector mechanisms,” Chem Immunol, 1997, 65:88-110. [cited by applicant]
Dillon et al., “Structural and Functional Characterization of Disulfide Isoforms of the Human IgG2 Subclass,” J Biol Chem, Jun. 6, 2008, 283(23):16206-16215. Epub Mar. 12, 2008. [cited by applicant]
Dubrot et al., “Treatment with anti-CD137 mAbs causes intense accumulations of liver T cells without selective antitumor immunotherapeutic effects in this organ,” Cancer Immunol Immunother, Aug. 2010, 59(8):1223-1233. [cited by applicant]
Ferran et al., “Cytokine-related syndrome following injection of anti-CD3 monoclonal antibody: Further evidence for transient in vivo T cell activation,” Eur J Immunol, Mar. 1990, 20(3):509-515. [cited by applicant]
Frey et al., “Cytokine release syndrome with novel therapeutics for acute lymphoblastic leukemia,” Hematology Am Soc Hematol Educ Program, Dec. 2, 2016, 2016(1):567-572. [cited by applicant]
Golay et al., “Design and Validation of a Novel Generic Platform for the Production of Tetravalent IgG1-like Bispecific Antibodies,” J Immunol, Apr. 1, 2016, 196(7):3199-3211. [cited by applicant]
Greenwood et al., “Structural motifs involved in human IgG antibody effector functions,” Eur J Immunol, May 1993, 23(5):1098-1104. [cited by applicant]
Hess et al., “Cancer therapy with trifunctional antibodies: linking innate and adaptive immunity,” Future Oncol, Jan. 2012, 8(1):73-85. doi: 10.2217/fon.11.138. [cited by applicant]
Hill et al., “Human antibody-based chemically induced dimerizers for cell therapeutic applications,” Nat Chem Biol, Feb. 2018, 14(2):112-117. doi:10.1038/nchembio.2529. [cited by applicant]
Houot et al., “Therapeutic effect of CD137 immunomodulation in lymphoma and its enhancement by T [cited by applicant]
Huet et al., “Multivalent nanobodies targeting death receptor 5 elicit superior tumor cell killing through efficient caspase induction,” mAbs, Nov./Dec. 2014, 6(6):1560-1570. [cited by applicant]
Igawa et al., “Antibody recycling by engineered pH-dependent antigen binding improves the duration of antigen neutralization,” Nat Biotechnol, Nov. 2010, 28(11):1203-1207. Epub Oct. 17, 2010. [cited by applicant]
Ishiguro et al., “An anti-glypican 3/CD3 bispecific T cell-redirecting antibody for treatment of solid tumors,” Sci Transl Med, Oct. 4, 2017, 9(410). pii: eaal4291. doi: 10.1126/scitranslmed.aal4291. [cited by applicant]
Jefferis et al., “Interaction sites on human IgG-Fc for Fc gamma R: current models,” Immunol Lett, Jun. 3, 2002, 82(1-2):57-65. [cited by applicant]
Jo et al., “Engineering therapeutic antibodies targeting G-protein-coupled receptors,” Exp Mol Med, Feb. 5, 2016, 48(2):e207. [cited by applicant]
Jones et al., “Growth factor receptor interplay and resistance in cancer,” Endocr Relat Cancer, Dec. 2006, 13 Suppl 1:S45-51. [cited by applicant]
Jong et al., “A Novel Platform for the Potentiation of Therapeutic Antibodies Based on Antigen-Dependent Formation of IgG Hexamers at the Cell Surface,” PLoS Biol, Jan. 6, 2016, 14(1):e1002344. [cited by applicant]
Kontermann, “Dual targeting strategies with bispecific antibodies,” mAbs, Mar.-Apr. 2012, 4(2):182-197. doi: 10.4161/mabs.4.2.19000. Epub Mar. 1, 2012. [cited by applicant]
Lazar et al., “Engineered antibody Fc variants with enhanced effector function,” Proc Natl Acad Sci USA, Mar. 2006, 103(11):4005-4010. Epub Mar. 6, 2006. [cited by applicant]
Lee et al., “Cell-type specific potent Wnt signaling blockade by bispecific antibody,” Sci Rep, Jan. 15, 2018, 8(1):766. [cited by applicant]
Li et al., “Antitumor activities of agonistic anti-TNFR antibodies require differential FcγRIIB coengagement in vivo,” Proc Natl Acad Sci USA, Nov. 26, 2013, 110(48):19501-19606. doi: 10.1073/pnas.1319502110. Epub Nov. … [cited by applicant]
Mimoto et al., “Fc Engineering to Improve the Function of Therapeutic Antibodies,” Curr Pharm Biotechnol, 2016, 17(15):1298-1314. doi: 10.2174/1389201017666160824161854. [cited by applicant]
Morgan et al., “The N-terminal end of the C [cited by applicant]
Mukai et al., “Codon reassignment in the Escherichia coli genetic code,” Nucleic Acids Res, Dec. 2010, 38(22):8188-8195. [cited by applicant]
Nimmerjahn et al., “Fcgamma receptors as regulators of immune responses,” Nat Rev Immunol, Jan. 2008, 8(1):34-47. [cited by applicant]
Orita et al., “A novel therapeutic approach for thrombocytopenia by minibody agonist of the thrombopoietin receptor,” Blood, Jan. 15, 2005, 105(2):562-566 [Epub Sep. 16, 2004]. [cited by applicant]
Pavlou et al., “The therapeutic antibodies market to 2008,” Eur J Pharm Biopharm, Apr. 2005, 59(3):389-396. [cited by applicant]
Peggs et al., “Cancer immunotherapy: co-stimulatory agonists and co-inhibitory agonists,” Clin Exp Immunol, Jul. 2009, 157(1):9-19. doi: 10.1111/j.1365-2249.2009.03912.x. Epub Feb. 18, 2009. [cited by applicant]
Porter et al., “Chimeric Antigen Receptor-Modified T Cells in Chronic Lymphoid Leukemia,” N Engl J Med, Aug. 25, 2011, 365(8):725-733. doi: 10.1056/NEJMoa1103849. Epub Aug. 10, 2011. [cited by applicant]
Rader, “DARTs take aim at BiTEs,” Blood, Apr. 28, 2011, 117(17):4403-4404. [cited by applicant]
Reichert et al., “Monoclonal antibody successes in the clinic,” Nat Biotechnol, Sep. 2005, 23(9):1073-1078. [cited by applicant]
Riechelmann et al., “Adoptive therapy of head and neck squamous cell carcinoma with antibody coated immune cells: a pilot clinical trial,” Cancer Immunol Immunother, Sep. 2007, 56(9):1397-1406. Epub Feb. 2, 2007. [cited by applicant]
Rothe et al., “Recombinant proteins in rheumatology—recent advances,” N Biotechnol, Sep. 2011, 28(5):502-510. doi: 10.1016/j.nbt.2011.03.019. Epub Apr. 5, 2011. [cited by applicant]
Schabowsky et al., “A Novel Form of 4-1BBL Has Better Immunomodulatory Activity than an Agonistic Anti-4-1BB Ab without Ab Associated Severe Toxicity,” Vaccine, Dec. 11, 2009, 28(2):512-522. doi: 10.1016/j.vaccine.2009.… [cited by applicant]
Scheer et al., “Reorienting the Fab Domains of Trastuzumab Results in Potent HER2 Activators,” PLoS One, Dec. 2012, 7(12):e51817. [cited by applicant]
Seimetz et al., “Development and approval of the trifunctional antibody catumaxomab (anti-EpCAM x anti-CD3) as a targeted cancer immunotherapy,” Cancer Treat Rev, Oct. 2010, 36(6):458-467. doi: 10.1016/j.ctrv.2010.03.00… [cited by applicant]
Shinkawa et al., “The absence of fucose but not the presence of galactose or bisecting N-acetylglucosamine of human IgG1 complex-type oligosaccharides shows the critical role of enhancing antibody-dependent cellular cyt… [cited by applicant]
Unkeless et al., “Structure and function of human and murine receptors for IgG,” Annu Rev Immunol, Apr. 1988, 6:251-281. [cited by applicant]
Vinay et al., “4-1BB signaling beyond T Cells,” Cell Mol Immunol, Jul. 2011, 8(4):281-284. doi: 10.1038/cmi.2010.82. Epub Jan. 10, 2011. [cited by applicant]
Wozniak-Knopp et al., “Introducing antigen-binding sites in structural loops of immunoglobulin constant domains: Fc fragments with engineered HER2/neu-binding sites and antibody properties,” Protein Eng Des Sel, Apr. 20… [cited by applicant]
Zeidler et al., “Simultaneous activation of T cells and accessory cells by a new class of intact bispecific antibody results in efficient tumor cell killing,” J Immunol, Aug. 1, 1999, 163(3):1246-1252. [cited by applicant]
Zhang et al., “Selection of antibodies that regulate phenotype from intracellular combinatorial antibody libraries,” Proc Natl Acad Sci USA, Sep. 25, 2012:109(39):15728-15733. [cited by applicant]
International Search Report and Written Opinion for App. Ser. No. PCT/JP2019/038087, mailed Dec. 24, 2019, 11 pages. [cited by applicant]
International Preliminary Report on Patentability in International Application No. PCT/JP2019/038087, dated Mar. 23, 2021, 8 pages. [cited by applicant]
Edwards et al., “The Remarkable Flexibility of the Human Antibody Repertoire; Isolation of Over One Thousand Different Antibodies to a Single Protein, BLyS,” J Mol Biol, Nov. 14, 2003, 334(1):103-118. [cited by applicant]
Lloyd et al., “Modelling the human immune response: performance of a 10 [cited by applicant]
Nezu, Chugai's Strategy for Drug Discovery Research, Dec. 9, 2019, 81 pages. [cited by applicant]
Piche-Nicholas et al., “Changes in complementarity-determining regions significantly alter IgG binding to the neonatal Fc receptor (FcRn) and pharmacokinetics,” mAbs, Jan. 2018, 10(1):81-94. [cited by applicant]
U.S. Appl. No. 17/797,540, Kawa, filed Aug. 4, 2022. [cited by applicant]
U.S. Appl. No. 17/797,540, filed Aug. 4, 2022, Kawa. [cited by applicant]
U.S. Appl. No. 18/436,917, Shimizu et al., Feb. 8, 2024. [cited by applicant]
U.S. Appl. No. 18/436,917, filed Feb. 8, 2024, Shimizu et al. [cited by applicant]
Jakob et al., “Structure reveals function of the dual variable domain immunoglobulin (DVD-Ig) molecule,” mAbs, May-Jun. 2013, 5(3):358-363. [cited by applicant]
Kinder et al., “Engineered Protease-resistant Antibodies with Selectable Cell-killing Functions,” The Journal of Biological Chemistry, Oct. 25, 2013, 288(43):30843-30854. [cited by applicant]
Pan et al., “Blocking Neuropilin-1 Function has an Additive Effect with Anti-VEGF to Inhibit Tumor Growth,” Cancer Cell, Jan. 2007, 11:53-67. [cited by applicant]
Wu et al., “Molecular construction and optimization of anti-human IL-1α/β dual variable domain immunoglobulin (DVD-Ig) molecules,” mAbs, Jul.-Aug. 2009, 1(4):339-347. doi: 10.4161/mabs.1.4.8755. [cited by applicant]
USPTO Non-Final Office Action in U.S. Appl. No. 17/264,388, dated Feb. 12, 2024, 21 pages. [cited by applicant]
U.S. Appl. No. 18/343,850, Naoi et al., filed Jun. 29, 2023. [cited by applicant]
U.S. Appl. No. 18/345,750, Igawa et al., filed Jun. 30, 2023. [cited by applicant]
U.S. Appl. No. 18/343,850, filed Jun. 29, 2023, Naoi et al. [cited by applicant]
U.S. Appl. No. 18/345,750, filed Jun. 30, 2023, Igawa et al. [cited by applicant]
U.S. Appl. No. 17/506,733, Igawa et al., filed Oct. 21, 2021. [cited by applicant]
U.S. Appl. No. 17/506,733, filed Oct. 21, 2021, Igawa et al. [cited by applicant]
Amann et al., “Therapeutic window of an EpCAM/CD3-specific BiTE antibody in mice is determined by a subpopulation of EpCAM-expressing lymphocytes that is absent in humans,” Cancer Immunol Immunother, Jan. 2009, 58(1):95… [cited by applicant]
Baeuerle et al., “Bispecific T-Cell Engaging Antibodies for Cancer Therapy,” Cancer Res, Jun. 15, 2009, 69(12):4941-4944. doi: 10.1158/0008-5472.CAN-09-0547. Epub Jun. 9, 2009. [cited by applicant]
Bardwell et al., “Potent and conditional redirected T cell killing of tumor cells using Half DVD-Ig,” Protein Cell, Jan. 2018, 9(1):121-129. [cited by applicant]
Beljaars et al., “The preferential homing of a platelet derived growth factor receptor-recognizing macromolecule to fibroblast-like cells in fibrotic tissue,” Biochemical Pharmacology, Oct. 2003, 66(7):1307-1317. [cited by applicant]
Berntzen et al., “Identification of a High Affinity FcγRIIA-binding Peptide that Distinguishes FcγRIIA from FcγRIIB and Exploits FcγRIIA-mediated Phagocytosis and Degradation,” J Biol Chem, Jan. 2009, 284(2): 1126-1135.… [cited by applicant]
Binetruy-Tournaire et al., “Identification of a peptide blocking vascular endothelial growth factor (VEGF)-mediated angiogenesis,” EMBO J, Apr. 3, 2000, 19(7):1525-1533. [cited by applicant]
Boder et al., “Directed evolution of antibody fragments with monovalent femtomolar antigen binding affinity,” Proc Natl Acad Sci USA, Sep. 26, 2000, 97(20):10701-10705. [cited by applicant]
Bostrom et al., “Variants of the Antibody Herceptin That Interact with HER2 and VEGF at the Antigen Binding Site,” Science, Mar. 20, 2009, 323(5921):1610-1614. [cited by applicant]
Brennand et al., “A cyclic peptide analogue of loop III of PDGF-BB causes an apoptosis in human fibroblasts,” FEBS Lett, Dec. 1997, 15, 419(2-3):166-170. [cited by applicant]
Bulman et al., “Mutations in the human Delta homologue, DLL3, cause axial skeletal defects in spondylocostal dysostosis,” Nat Genet, Apr. 2000, 24(4):438-441. [cited by applicant]
Campoli et al., “Immunotherapy of Malignant Disease with Tumor Antigen-Specific Monoclonal Antibodies,” Clin Cancer Res, Jan. 1, 2010, 16(1):11-20. Epub Dec. 22, 2009. [cited by applicant]
Chamarthy et al., “Gene delivery to dendritic cells facilitated by a tumor necrosis factor alpha-competing peptide,” Mol Immunol, Jul. 2004, 41(8):741-749. [cited by applicant]
Chen et al., “Characterization of human IgG repertoires in an acute HIV-1 infection,” Exp Mol Pathol, Dec. 2012, 93(3):399-407. doi: 10.1016/j.yexmp.2012.09.022. Epub Oct. 1, 2012. [cited by applicant]
Chen et al., “Enhancement and destruction of antibody function by somatic mutation: unequal occurrence is controlled by V gene combinatorial associations,” The EMBO Journal, Jun. 1995, 14(12):2784-2794. [cited by applicant]
Conrad et al., “TCR and CD3 antibody cross-reactivity in 44 species,” Cytometry A, Nov. 2007, 71(11):925-933. [cited by applicant]
Dall'Acqua et al., “Modulation of the Effector Functions of a Human IgG1 through Engineering of Its Hinge Region,” J Immunol, Jul. 15, 2006, 177(2):1129-1138. [cited by applicant]
De Pascalis et al., “Grafting of ‘Abbreviated’ Complementarity-Determining Regions Containing Specificity-Determining Residues Essential for Ligand Contact to Engineer a Less Immunogenic Humanized Monoclonal Antibody,” … [cited by applicant]
Deambrosis et al., “Inhibition of CD40-CD154 costimulatory pathway by a cyclic peptide targeting CD154,” J Mol Med, Feb. 2009, 87(2):181-197. [cited by applicant]
Dermer et al., “Another Anniversary for the War on Cancer,” Bio/Technology, Mar. 12, 1994, 12:320. [cited by applicant]
Dickopf et al., “Format and geometries matter: Structure-based design defines the functionality of bispecific antibodies,” Comput Struct Biotechnol J, May 14, 2020, 18:1221-1227. [cited by applicant]
Dreier et al., “Extremely Potent, Rapid and Costimulation-Independent Cytotoxic T-Cell Response Against Lymphoma Cells Catalyzed by a Single-Chain Bispecific Antibody,” Int J Cancer, Aug. 20, 2002, 100(6):690-697. [cited by applicant]
Dufner, “Harnessing phage and ribosome display for antibody optimization,” Trends Biotechnol, Nov. 2006, 24(11):523-529. [cited by applicant]
Eigenbrot et al., “Two-in-One antibodies with dual action Fabs,” Curr Opin Chem Biol, Jun. 2013, 17(3):400-405. doi: 10.1016/j.cbpa.2013.04.015. Epub May 14, 2013. [cited by applicant]
Ellmark et al., “Selective FcγR engagement by human agonistic anti-CD40 antibodies,” Transl Cancer Res, 2016, 5(Suppl 4):S839-S841. [cited by applicant]
Faham et al., “Antigen-Containing Liposomes Engrafted with Flagellin-Related Peptides Are Effective Vaccines That Can Induce Potent Antitumor Immunity and Immunotherapeutic Effect,” J Immunol, Jul. 2010, 2010, 185:1744-… [cited by applicant]
Fukuda et al., “In vitro evolution of single-chain antibodies using mRNA display,” Nucleic Acids Res, Nov. 2006, 34(19):e127, 8 pages. [cited by applicant]
Gura et al., “Systems for Identifying New Drugs Are Often Faulty,” Science, Nov. 7, 1997, 278:1041-1042. [cited by applicant]
Hanes et al., “Picomolar affinity antibodies from a fully synthetic naïve library selected and evolved by ribosome display,” Nat Biotechnol, Dec. 2000, 18(12):1287-1292. [cited by applicant]
Harvey et al., “Anchored periplasmic expression, a versatile technology for the isolation of high-affinity antibodies from [cited by applicant]
Hawkins et al., “Selection of Phage Antibodies by Binding Affinity—Mimicking Affinity Maturation,” J Mol Biol, Aug. 5, 1992, 226(3):889-896. [cited by applicant]
Hetian et al., “A Novel Peptide Isolated from a Phage Display Library Inhibits Tumor Growth and Metastasis by Blocking the Binding of Vascular Endothelial Growth Factor to Its Kinase Domain Receptor,” J Biol Chem, Nov. … [cited by applicant]
Hezareh et al., “Effector Function Activities of a Panel of Mutants of a Broadly Neutralizing Antibody against Human Immunodeficiency Virus Type 1,” J Virol, Dec. 2001, 75(24):12161-12168. [cited by applicant]
Holen et al., “Activation of EphA receptors on CD47CD45R07 memory cells stimulates migration,” J Leukoc Biol, Jun. 2010, 87(6):1059-1068. doi: 10.1189/j1b.0709497. Epub Feb. 16, 2010. [cited by applicant]
Ikuta et al., “Expression of human immunodeficiency virus type 1 (HIV-1) gag antigens on the surface of a cell line persistently infected with HIV-1 that highly expresses HIV-1 antigens,” Virology, Jun. 1989, 170(2):408… [cited by applicant]
Kraft et al., “Definition of an Unexpected Ligand Recognition Motif for αvβ6 Integrin,” J Biol Chem, Jan. 22, 1999, 274:1979-1985. [cited by applicant]
Kramer et al., “Molecular basis for the binding promiscuity of an anti-p24 (HIV-1) monoclonal antibody” Cell, Dec. 12, 1997, 91(6):799-809. [cited by applicant]
Kronqvist et al., “A novel affinity protein selection system based on staphylococcal cell surface display and flow cytometry,” Protein Eng Des Sel, Apr. 2008, 21(4):247-255. [cited by applicant]
Kussie et al., “A Single Engineered Amino Acid Substitution Changes Antibody Fine Specificity,” J Immunol, Jan. 1, 1994, 152(1):146-152. [cited by applicant]
Lederman et al., “A Single Amino Acid Substitution in a Common African Allele of the CD4 Molecule Ablates Binding of the Monoclonal Antibody, OKT4,” Mol Immunol, Nov. 1991, 28(11):1171-1181. [cited by applicant]
Li et al., “β-Endorphin omission analogs: Dissociation of immunoreactivity from other biological activities,” Proc Natl Acad Sci USA, 1980, 77:3211-3214. [cited by applicant]
Li et al., Activation of the Proapoptotic Death Receptor DR5 by Oligomeric Peptide and Antibody Agonists, J Mol Biol, Aug. 18, 2006, 361(3):522-536. [cited by applicant]
Lightfield et al., “Critical function for Naip5 in inflammasome activation by a conserved carboxy-terminal domain of flagellin,” Nat Immunol, Oct. 2008, 9(10):1171-1178. doi: 10.1038/ni.1646. Epub Aug. 24, 2008. [cited by applicant]
Lum et al., “Targeting T Cells with Bispecific Antibodies for Cancer Therapy,” BioDrugs, Dec. 1, 2011, 25(6):365-379. doi:10.2165/11595950-000000000-00000. [cited by applicant]
Lutterbuese et al., “T cell-engaging BiTE antibodies specific for EGFR potently eliminate KRAS- and BRAF-mutated colorectal cancer cells,” Pro Natl Acad Sci USA, Jul. 13, 2010, 107(28):12605-12610. doi: 10.1073/pnas.100… [cited by applicant]
MacCallum et al., “Antibody-antigen Interactions: Contact Analysis and Binding Site Topography,” J Mol Biol, Oct. 11, 1996, 262(5):732-745. [cited by applicant]
Mack et al., “A small bispecific antibody construct expressed as a functional single-chain molecule with high tumor cell cytotoxicity,” Proc Natl Acad Sci USA, Jul. 18, 1995, 92(15):7021-7025. [cited by applicant]
Marks et al., “By-passing Immunization—Human Antibodies from V-gene Libraries Displayed on Phage,” J Mol Biol, Dec. 5, 1991, 222(3):581-597. [cited by applicant]
Mezzanzanica et al., “Human Ovarian Carcinoma Lysis by Cytotoxic T Cells Targeted by Bispecific Monoclonal Antibodies: Analysis of the Antibody Components,” Int J Cancer, Apr. 15, 1988, 41(4):609-615. [cited by applicant]
Mullendore et al., “Ligand-dependent Notch Signaling is Involved in Tumor Initiation and Tumor Maintenance in Pancreatic Cancer,” Clin Cancer Res, Apr. 1, 2009, 15(7):2291-2301. [cited by applicant]
Nakamura et al., “Peptide mimics of epidermal growth factor (EGF) with antagonistic activity,” Journal of Biotechnology, Mar. 30, 2005, 116(3): 211-219. [cited by applicant]
Odegrip et al., “CIS display: In vitro selection of peptides from libraries of protein-DNA complexes,” Proc Natl Acad Sci USA, Mar. 2, 2004, 101(9):2806-2810. [cited by applicant]
Phillips et al., “Molecular subclasses of high-grade glioma predict prognosis, delineate a pattern of disease progression, and resemble stages in neurogenesis,” Cancer Cell, Mar. 2006, 9(3):157-173. [cited by applicant]
Rao et al., “Novel cyclic and linear oligopeptides that bind to integrin β1 chain and either inhibit or costimulate T lymphocytes,” Int Immunopharmacol, Mar. 2003, 3(3):435-443. [cited by applicant]
Richards et al., “A peptide containing a novel FPGN CD40-binding sequence enhances adenoviral infection of murine and human dendritic cells,” Eur J Biochem, May 2003, 270(10):2287-2294. [cited by applicant]
Rudikoff et al., “Single amino acid substitution altering antigen-binding specificity,” Proc Natl Acad Sci USA, Mar. 1982, 79(6):1979-1983. [cited by applicant]
Schaefer et al., “A two-in-one antibody against HER3 and EGFR has superior inhibitory activity compared with monospecific antibodies,” Cancer Cell, Oct. 18, 2011, 20(4):472-486. doi: 10.1016/j.ccr.2011.09.003. [cited by applicant]
Schlereth et al., “T-cell activation and B-cell depletion in chimpanzees treated with a bispecific anti-CD19/anti-CD3 single-chain antibody construct,” Cancer Immunol Immunother, May 2006, 55(5):503-514. Epub Jul. 20, 2… [cited by applicant]
Schraa et al., RGD-Modified Anti-CD3 Antibodies Redirect Cytolytic Capacity of Cytotoxic T Lymphocytes Toward αvβ3-Expressing Endothelial Cells, Int J Cancer, Nov. 1, 2004, 112(2):279-285. [cited by applicant]
Sebastian et al., “Treatment of non-small cell lung cancer patients with the trifunctional monoclonal antibody catumaxomab (anti-EpCAM x anti-CD3): a phase I study,” Cancer Immunol Immunother, Oct. 2007, 56(10):1637-164… [cited by applicant]
Sepp et al., “Cell-Free Selection of Domain Antibodies by in vitro Compartmentalization,” Methods Mol Biol, Jul. 2012, 911:183-198. [cited by applicant]
Shanmugam et al., “Synthetic Toll Like Receptor-4 (TLR-4) Agonist Peptides as a Novel Class of Adjuvants,” PLoS One, Feb. 2012, 7(2):e30839. [cited by applicant]
Staerz et al., “Hybrid antibodies can target sites for attack by T cells,” Nature, Apr. 18-24, 1985, 314(6012):628-631. [cited by applicant]
Staerz et al., “Hybrid hybridoma producing a bispecific monoclonal antibody that can focus effector T-cell activity,” Proc Natl Acad Sci USA, Mar. 1986, 83(5):1453-1457. [cited by applicant]
Stancovski et al., “Mechanistic Aspects of the Opposing Effects of Monoclonal Antibodies to the ERBB2 Receptor on Tumor Growth,” Proc Nat Acad Sci USA, Oct. 1, 1991, 88(19):8691-8695. [cited by applicant]
Traxlmayr et al., “Integrin binding human antibody constant domains—Probing the C-terminal structural loops for grafting the RGD motif,” J Biotechnol, Sep. 10, 2011, 155(2):193-202. doi: 10.1016/j.jbiotec.2011.06.042. E… [cited by applicant]
Turnpenny et al., “Novel mutations in DLL3, a somitogenesis gene encoding a ligand for the Notch signaling pathway, cause a consistent pattern of abnormal vertebral segmentation in spondylocostal dysostosis,” J Med Gene… [cited by applicant]
Tutt et al., “Trispecific F(ab′)3 derivatives that use cooperative signaling via the TCR/CD3 complex and CD2 to activate and redirect resting cytotoxic T cells,” J Immunol, Jul. 1, 1991, 147(1):60-69. [cited by applicant]
Vajdos et al., “Comprehensive Functional Maps of the Antigen-binding Site of an Anti-ErbB2 Antibody Obtained with Shotgun Scanning Mutagenesis,” J Mol Biol, Jul. 5, 2002, 320(2):415-428. [cited by applicant]
Vaughan et al., “Human Antibodies with Sub-nanomolar Affinities Isolated from a Large Non-immunized Phage Display Library,” Nat Biotechnol, Mar. 1996, 14(3):309-314. [cited by applicant]
Witte et al., “Monoclonal antibodies targeting the VEGF receptor-2 (Flk1/KDR) as an anti-angiogenic therapeutic strategy,” Cancer and Metastasis Reviews, Jun. 1998, 17(2):155-161. [cited by applicant]
Wolf et al., “BiTEs: bispecific antibody constructs with unique anti-tumor activity,” Drug Discov Today, Sep. 15, 2005, 10(18):1237-1244. [cited by applicant]
Wu et al., “Humanization of a Murine Monoclonal Antibody by Simultaneous Optimization of Framework and CDR Residues,” J Mol Biol, Nov. 19, 1999, 294(1):151-162. [cited by applicant]
Wu et al., “Structures of the CXCR4 Chemokine GPCR with Small-Molecule and Cyclic Peptide Antagonists,” Science, Nov. 19, 2010, 330:1066-1071. [cited by applicant]
Yu et al., “Interaction between Bevacizumab and Murine VEGF-A: A Reassessment,” Investigative Ophthalmology and Visual Science, Feb. 2008, 49(2):522-527. [cited by applicant]
Zhou et al., “Development of a novel mammalian cell surface antibody display platform,” mAbs, Sep.-Oct. 2010, 2(5):508-518. [cited by applicant]
U.S. Appl. No. 17/914,432, Chichili et al., filed Sep. 26, 2022. [cited by applicant]
U.S. Appl. No. 17/914,432, filed Sep. 26, 2022 Chichili et al. [cited by applicant]
Garber et al., “Bispecific antibodies rise again,” Nat Rev Drug Discov, Nov. 2014, 13(11):799-801. [cited by applicant]
Chiu et al., “Antibody Structure and Function: The Basis for Engineering Therapeutics,” Antibodies, 2019, 8(55):1-80. [cited by applicant]
Diamond et al., “Somatic mutation of the T15 heavy chain gives rise to an antibody with autoantibody specificity,” Proc Natl Acad Sci USA, Sep. 1984, 81(18):5841-5844. [cited by applicant]
Dirks, “Brain tumor stem cells: bringing order to the chaos of brain cancer,” J Clin Oncol, Jun. 10, 2008, 26(17):2916-2924. [cited by applicant]
Kuznetsova, “Brackets in text of legal document as a linguo-cognitive phenomenon,” Bulletin MGOU, Chapter—Russian Philology, 2015, 3:37-43 (with English translation). [cited by applicant]
Lopez-Lazaro et al., “The migration ability of stem cells can explain the existence of cancer of unknown primary site. Rethinking metastasis,” Oncoscience, May 1, 2015, 2(5):467-475. [cited by applicant]
Mabey, “Epidemiology of sexually transmitted infections: worldwide,” Medicine, 2014, 42(6):287-290. [cited by applicant]
Mariuzza et al., “The Structural Basis of Antigen-Antibody Recognition,” Annu Rev Biophys Biophys Chem, 1987, 16:139-159. [cited by applicant]
Ohno et al., “Antigen-binding specificities of antibodies are primarily determined by seven residues of V [cited by applicant]
Roitt et al., “Antibody Structure and Function,” Immunology, Moscow, Mir, 2000, pp. 110-111 (with what are believed to be the corresponding pages from an English version of Immunology). [cited by applicant]
Rudzitis et al., Chemistry—Inorganic chemistry—8th grade, 2011, p. 15 (with English translation). [cited by applicant]
Singer et al., “The Genetic Molecules,” Genes & Genomes, Moscow, Mir, 1998, pp. 63-64 (with what are believed to be the corresponding pages from an English version of Genes & Genomes). [cited by applicant]
Solopova et al., “Bispecific Antibodies in Clinical Practice and Clinical Trials (Literature Review),” Clinical Oncohematology, 2019, 12(2):125-144 (with English translation). [cited by applicant]
Sundberg, “Structural basis of antibody-antigen interactions,” Methods Mol Biol, 2009, 524:23-36. [cited by applicant]
Torres et al., “The immunoglobulin constant region contributes to affinity and specificity,” Trends Immunol, Feb. 2008, 29(2):91-97. doi: 10.1016/j.it.2007.11.004. Epub Jan. 10, 2008. PMID: 18191616. [cited by applicant]
Tran et al., “Survival comparison between glioblastoma multiforme and other incurable cancers,” J Clin Neurosci, Apr. 2010,17(4):417-421. [cited by applicant]
Yarilin, Fundamentals of Immunology, Moscow, Medicina, 1999, pp. 172-174 (with English translation). [cited by applicant]
Domingues et al., “Melanoma treatment in review,” Immunotargets Ther, Jun. 7, 2018, 7:35-49. [cited by applicant]
Guselnikova et al., “NeuN as a Neuronal Nuclear Antigen and Neuron Differentiation Marker,” Acta Naturae, 2015, 2(25):46-51 (with English translation). [cited by applicant]
Kadnikova et al., “Capsular Antigen of [cited by applicant]
Tarantul, “Antigen,” Explanatory Biotechnological Dictionary—Russian-English, Moscow, 2009, p. 66 (with English translation). [cited by applicant]
Wang et al., “Silence of MCL-1 upstream signaling by shRNA abrogates multiple myeloma growth,” Exp Hematol Oncol, Nov. 19, 2014, 3(1):27, 7 pages. [cited by applicant]
Zajcev et al., “Prostate-specific antigen (PSA) in the diagnosis of prostate cancer,” Polyclinics, 2012, 4-3:55-58 (with English abstract). [cited by applicant]
U.S. Appl. No. 17/670,917, Naoi et al., filed Feb. 14, 2022. [cited by applicant]
U.S. Appl. No. 17/670,917, filed Feb. 14, 2022, Naoi et al. [cited by applicant]
Liu et al., “Fine mapping of the antigen-antibody interaction of scFv215, a recombinant antibody inhibiting RNA polymerase II from [cited by applicant]
Wong et al., “Structural requirements for a specificity switch and for maintenance of affinity using mutational analysis of a phage-displayed anti-arsonate antibody of Fab heavy chain first complementarity-determining r… [cited by applicant]
U.S. Appl. No. 18/696,717, Naoi et al., filed Mar. 28, 2024. [cited by applicant]
U.S. Appl. No. 18/654,675, Naoi et al., filed May 3, 2024. [cited by applicant]
U.S. Appl. No. 18/696,717, filed Mar. 28, 2024, Naoi et al. [cited by applicant]
U.S. Appl. No. 18/654,675, filed May 3, 2024, Naoi et al. [cited by applicant]
Labrijn et al., “Bispecific antibodies: a mechanistic review of the pipeline,” Nat Rev Drug Discov, Aug. 2019, 18(8):585-608. [cited by applicant]
Mikami et al., “Abstract 1872: A DLL3/CD3/CD137 trispecific T cell engager shows potent antitumor activity in small cell lung cancer models,” Cancer Res, Apr. 4, 2023, 83(7_Supplement):1872, 1 page. [cited by applicant]
Rudin et al., “Emerging therapies targeting the delta-like ligand 3 (DLL3) in small cell lung cancer,” J Hematol Oncol, Jun. 24, 2023, 16(1):66, 21 pages. [cited by applicant]
Wu et al., “Building blocks for bispecific and trispecific antibodies,” Methods, Feb. 1, 2019, 154:3-9. [cited by applicant]
U.S. Appl. No. 17/914,855, filed Sep. 27, 2022, Naoi et al. [cited by applicant]
Grujic et al., “Impact of antibody subclass and disulfide isoform differences on the biological activity of CD200R and Bklotho agonist antibodies,” Biochem Biophys Res Commun, May 13, 2017, 486(4):985-991. [cited by applicant]
Kirley et al., “Selective disulfide reduction for labeling and enhancement of Fab antibody fragments,” Biochem Biophys Res Commun, Nov. 25, 2016, 480(4):752-757. [cited by applicant]
Moritz et al., “Assessment of disulfide and hinge modifications in monoclonal antibodies,” Electrophoresis, Mar. 2017, 38(6):769-785. [cited by applicant]
Shen et al., “Single variable domain-IgG fusion. A novel recombinant approach to Fc domain-containing bispecific antibodies,” J Biol Chem, Apr. 21, 2006, 281(16):10706-10714. [cited by applicant]
Vaks et al., “Design Principles for Bispecific IgGs, Opportunities and Pitfalls of Artificial Disulfide Bonds,” Antibodies, Jul. 28, 2018, 7(3):27, 28 pages. [cited by applicant]
USPTO Final Office Action in U.S. Appl. No. 17/264,388, dated Aug. 1, 2024, 26 pages. [cited by applicant]
Chen et al., “Bispecific antibodies in cancer immunotherapy,” Hum Vaccin Immunother, Oct. 2, 2016, 12(10):2491-2500. doi: 10.1080/21645515.2016.1187802. Epub Jun. 1, 2016. [cited by applicant]