IP Library › Granted Patent US 12,617,854
Granted Patent B2
US 12,617,854 · App. 17/739,934 · Granted May 5, 2026

Humanized or chimeric CD3 antibodies

Inventors: Rik Rademaker (Utrecht, NL); Isil Altintas (Utrecht, NL); Patrick Engelberts (Utrecht, NL); Janine Schuurman (Utrecht, NL); Paul Parren (Utrecht, NL)
Assignee: GENMAB A/S
C07K16/2809C07K16/32A61K2039/505C07K2317/24C07K2317/31C07K2317/526C07K2317/55C07K2317/565C07K2317/73C07K2317/92
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 12,617,854
App. No.
17/739,934
Granted
May 5, 2026
Kind
B2
Abstract

The present invention relates to humanized or chimeric antibodies binding CD3. It furthermore relates to bispecific antibodies, compositions, pharmaceutical compositions, use of said antibodies in the treatment of a disease, and method of treatment.

Claims (51)

1 . A nucleic acid, or set of nucleic acids, encoding a humanized or chimeric antibody which binds to human CD3, wherein said antibody comprises a heavy chain variable (VH) region and a light chain variable (VL) region, wherein:

a) the VH region comprises the CDR1, CDR2 and CDR3 sequences set forth in SEQ ID NOs: 1, 2, and 176, respectively, and the VL region comprises the CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NO: 6, the sequence GTN, and SEQ ID NO: 7, respectively;

b) the VH region comprises the CDR1, CDR2 and CDR3 sequences set forth in SEQ ID NOs: 1, 2, and 184, respectively, and the VL region comprises the CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NO: 6, the sequence GTN, and SEQ ID NO: 7, respectively;

c) the VH region comprises the CDR1, CDR2 and CDR3 sequences set forth in SEQ ID NOs: 1, 2, and 220, respectively, and the VL region comprises the CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NO: 6, the sequence GTN, and SEQ ID NO: 7, respectively;

d) the VH region comprises the CDR1, CDR2 and CDR3 sequences set forth in SEQ ID NOs: 1, 2, and 236, respectively, and the VL region comprises the CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NO: 6, the sequence GTN, and SEQ ID NO: 7, respectively; or

e) the VH region comprises the CDR1, CDR2 and CDR3 sequences set forth in SEQ ID NOs: 1, 2, and 244, respectively, and the VL region comprises the CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NO: 6, the sequence GTN, and SEQ ID NO: 7, respectively.

2 . The nucleic acid, or set of nucleic acids, according to claim 1 , wherein the antibody comprises a VH region comprising the CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 1, 2, and 176, respectively, and a VL region comprising the CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NO: 6, the sequence GTN, and SEQ ID NO: 7, respectively.

3 . The nucleic acid, or set of nucleic acids, according to claim 1 , wherein the antibody is a full-length antibody.

4 . The nucleic acid, or set of nucleic acids, according to claim 1 , wherein the antibody is chimeric or humanized.

5 . The nucleic acid, or set of nucleic acids, according to claim 1 , wherein the antibody is of an isotype selected from the group consisting of IgG1, IgG2, IgG3, and IgG4.

6 . The nucleic acid, or set of nucleic acids, according to claim 1 , wherein the antibody comprises:

a) a VH region comprising the amino acid sequence set forth in SEQ ID NO: 177 and a VL region comprising the amino acid sequence set forth in SEQ ID NO: 8,

b) a VH region comprising the amino acid sequence set forth in SEQ ID NO: 185 and a VL region comprising the amino acid sequence set forth in SEQ ID NO: 8,

c) a VH region comprising the amino acid sequence set forth in SEQ ID NO: 221 and a VL region comprising the amino acid sequence set forth in SEQ ID NO: 8,

d) a VH region comprising the amino acid sequence set forth in SEQ ID NO: 237 and a VL region comprising the amino acid sequence set forth in SEQ ID NO: 8, or

e) a VH region comprising the amino acid sequence set forth in SEQ ID NO: 245 and a VL region comprising the amino acid sequence set forth in SEQ ID NO: 8.

7 . The nucleic acid, or set of nucleic acids, according to claim 6 , wherein the antibody comprises a VH region comprising the amino acid sequence set forth in SEQ ID NO: 177 and a VL region comprising the amino acid sequence set forth in SEQ ID NO: 8.

8 . An expression vector, or set of expression vectors, comprising the nucleic acid, or set of nucleic acids, according to claim 6 .

9 . A host cell comprising the expression vector, or set of expression vectors, according to claim 8 .

10 . A host cell comprising the nucleic acid, or set of nucleic acids, according to claim 6 .

11 . The nucleic acid, or set of nucleic acids, according to claim 1 , wherein the antibody is monovalent, bivalent or multivalent.

12 . The nucleic acid, or set of nucleic acids, according to claim 1 , wherein the antibody comprises a first heavy chain and a second heavy chain.

13 . The nucleic acid, or set of nucleic acids, according to claim 1 , wherein the antibody comprises a first heavy chain and a second heavy chain, wherein in at least one of said first and second heavy chains, one or more amino acids in the positions corresponding to positions L234, L235, D265, N297, and P331 in a human IgG1 heavy chain according to EU numbering, are not L, L, D, N, and P, respectively.

14 . The nucleic acid, or set of nucleic acids, according to claim 12 , wherein in at least one of said first and second heavy chains of the antibody,

(a) the amino acid in the position corresponding to position D265 in a human IgG1 heavy chain is not D;

(b) the amino acid in the position corresponding to position N297 in a human IgG1 heavy chain is not N;

(c) the amino acids in the positions corresponding to positions L234 and L235 in a human IgG1 heavy chain are not L and L, respectively;

(d) the amino acids in the positions corresponding to positions L234 and L235 in a human IgG1 heavy chain are F and E; or A and A, respectively;

(e) the amino acids in the positions corresponding to positions L234 and L235 in a human IgG1 heavy chain are F and E, respectively;

(f) the amino acids in the positions corresponding to positions L234 and L235 in a human IgG1 heavy chain are A and A, respectively;

(g) the amino acids in the positions corresponding to positions L234, L235, and D265 in a human IgG1 heavy chain are not L, L, and D, respectively;

(h) the amino acids in the positions corresponding to positions L234, L235, and D265 in a human IgG1 heavy chain are F, E, and A; or A, A, and A, respectively;

(i) the amino acids in the positions corresponding to positions L234, L235, and D265 in a human IgG1 heavy chain are F, E, and A, respectively;

(j) the amino acids in the positions corresponding to positions L234, L235, and D265 in a human IgG1 heavy chain, are A, A, and A, respectively; or

(k) the amino acids in the positions corresponding to positions L234, L235, D265, N297, and P331 in a human IgG1 heavy chain are F, E, A, Q, and S, respectively.

15 . The nucleic acid, or set of nucleic acids, according to claim 12 , wherein each of said first and second heavy chain of the antibody comprises at least a hinge region, a CH2 region, and a CH3 region, wherein in said first heavy chain, at least one of the amino acids in the positions corresponding to a position selected from the group consisting of T366, L368, K370, D399, F405, Y407, and K409 in a human IgG1 heavy chain has been substituted, and in said second heavy chain, at least one of the amino acids in the positions corresponding to a position selected from the group consisting of T366, L368, K370, D399, F405, Y407, and K409 in a human IgG1 heavy chain has been substituted, and wherein said first and said second heavy chains are not substituted in the same positions.

16 . The nucleic acid, or set of nucleic acids, according to claim 15 , wherein (a) the amino acid in the position corresponding to F405 in a human IgG1 heavy chain is L in said first heavy chain, and the amino acid in the position corresponding to K409 in a human IgG1 heavy chain is R in said second heavy chain, or (b) the amino acid in the position corresponding to F405 in a human IgG1 heavy chain is L in said second heavy chain, and the amino acid in the position corresponding to K409 in a human IgG1 heavy chain is R in said first heavy chain.

17 . An expression vector, or set of expression vectors, comprising the nucleic acid, or set of nucleic acids, according to claim 1 .

18 . A host cell comprising the expression vector, or set of expression vectors, according to claim 17 .

19 . A host cell comprising the nucleic acid, or set of nucleic acids, according to claim 1 .

20 . The host cell according to claim 19 , wherein the host cell is a recombinant eukaryotic, recombinant prokaryotic, or recombinant microbial host cell.

21 . The nucleic acid, or set of nucleic acids, according to claim 1 , wherein the antibody comprises:

a) a VH region comprising the amino acid sequence set forth in SEQ ID NO: 177 and a VL region comprising the amino acid sequence set forth in SEQ ID NO: 10,

b) a VH region comprising the amino acid sequence set forth in SEQ ID NO: 185 and a VL region comprising the amino acid sequence set forth in SEQ ID NO: 10,

c) a VH region comprising the amino acid sequence set forth in SEQ ID NO: 221 and a VL region comprising the amino acid sequence set forth in SEQ ID NO: 10,

d) a VH region comprising the amino acid sequence set forth in SEQ ID NO: 237 and a VL region comprising the amino acid sequence set forth in SEQ ID NO: 10, or

e) a VH region comprising the amino acid sequence set forth in SEQ ID NO: 245 and a VL region comprising the amino acid sequence set forth in SEQ ID NO: 10.

22 . The nucleic acid, or set of nucleic acids, according to claim 21 , wherein the antibody comprises a VH region comprising the amino acid sequence set forth in SEQ ID NO: 177 and a VL region comprising the amino acid sequence set forth in SEQ ID NO: 10.

23 . An expression vector, or set of expression vectors, comprising the nucleic acid, or set of nucleic acids, according to claim 21 .

24 . A host cell comprising the expression vector, or set of expression vectors, according to claim 23 .

25 . A host cell comprising the nucleic acid, or set of nucleic acids, according to claim 21 .

Assignments (3)
SECURITY INTEREST Recorded Dec 15, 2025
From: GENMAB A/S; GENMAB B.V.; GENMAB HOLDING B.V.
To: MORGAN STANLEY SENIOR FUNDING, INC.
Reel/Frame 073933/0597 →
NOTICE OF GRANT OF SECURITY INTEREST IN PATENTS Recorded Dec 15, 2025
From: GENMAB HOLDING B.V.; GENMAB A/S; GENMAB B.V.
To: WILMINGTON TRUST, NATIONAL ASSOCIATION
Reel/Frame 073949/0722 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded May 10, 2022
From: RADEMAKER, RIK; ALTINTAS, ISIL; ENGELBERTS, PATRICK; SCHUURMAN, JANINE; PARREN, PAUL
To: GENMAB A/S
Reel/Frame 059885/0325 →
Priority Claims (4)
DK PA 2015 00414 · Jul 15, 2015 · national
DK PA201500413 · Jul 15, 2015 · national
DK PA201500416 · Jul 16, 2015 · national
WO PCT/EP2016/050296 · Jan 8, 2016 · international
Continuity (2)
Division 15744317
Related Publication 20230027394A1 · Jan 26, 2023
References Cited (193)
US 4699880A · Goldstein · 1987 [cited by applicant]
US 5057313A · Shih et al. · 1991 [cited by applicant]
US 5589466A · Felgner et al. · 1996 [cited by applicant]
US 5973972A · Kwon et al. · 1999 [cited by applicant]
US 6077835A · Hanson et al. · 2000 [cited by applicant]
US 6331175B1 · Goldenberg · 2001 [cited by applicant]
US 7262028B2 · Van Berkel et al. · 2007 [cited by applicant]
US 7612181B2 · Wu et al. · 2009 [cited by applicant]
US 7951918B2 · Glaser et al. · 2011 [cited by applicant]
US 8236308B2 · Kischel et al. · 2012 [cited by applicant]
US 9150663B2 · Labrijn et al. · 2015 [cited by applicant]
US 9212230B2 · Schuurman et al. · 2015 [cited by applicant]
US 10344050B2 · Gramer et al. · 2019 [cited by applicant]
US 10407501B2 · Van Den Brink et al. · 2019 [cited by applicant]
US 10465006B2 · Van Den Brink et al. · 2019 [cited by applicant]
US 10544220B2 · Engelberts et al. · 2020 [cited by applicant]
US 10590206B2 · Labrijn et al. · 2020 [cited by applicant]
US 10597464B2 · Labrijn et al. · 2020 [cited by applicant]
US 10906991B2 · Schuurman et al. · 2021 [cited by applicant]
US 11008399B2 · Satijn et al. · 2021 [cited by applicant]
US 11180572B2 · De Jong et al. · 2021 [cited by applicant]
US 11261254B1 · Koopman et al. · 2022 [cited by applicant]
US 11359015B2 · Rademaker et al. · 2022 [cited by applicant]
US 11485796B2 · Labrijn et al. · 2022 [cited by applicant]
US 11492371B2 · Gramer et al. · 2022 [cited by applicant]
US 11613575B2 · Van Den Brink et al. · 2023 [cited by applicant]
US 11866514B2 · Labrijn et al. · 2024 [cited by applicant]
US 11970544B2 · Satijn et al. · 2024 [cited by applicant]
US 20100105874A1 · Schuurman et al. · 2010 [cited by applicant]
US 20100155133A1 · Makwinski et al. · 2010 [cited by applicant]
US 20100226923A1 · Rao et al. · 2010 [cited by applicant]
US 20130039913A1 · Labrijn et al. · 2013 [cited by applicant]
US 20140303356A1 · Gramer et al. · 2014 [cited by applicant]
US 20150175707A1 · De Jong et al. · 2015 [cited by applicant]
US 20150337049A1 · Abrijn et al. · 2015 [cited by applicant]
US 20160046727A1 · Labrijn et al. · 2016 [cited by applicant]
US 20160159930A1 · Schuurman et al. · 2016 [cited by applicant]
US 20160168247A1 · Van Den Brink et al. · 2016 [cited by applicant]
US 20160333095A1 · Van Den Brink et al. · 2016 [cited by applicant]
US 20170233497A1 · Labrijn et al. · 2017 [cited by applicant]
US 20170355767A1 · Engelberts et al. · 2017 [cited by applicant]
US 20190284278A1 · Rademaker et al. · 2019 [cited by applicant]
US 20200048304A1 · Gramer et al. · 2020 [cited by applicant]
US 20200123255A1 · Van Den Brink et al. · 2020 [cited by applicant]
US 20200199229A1 · Van Den Brink et al. · 2020 [cited by applicant]
US 20200199231A1 · Engelberts et al. · 2020 [cited by applicant]
US 20200262932A1 · Labrijn et al. · 2020 [cited by applicant]
US 20200277397A1 · Satijn et al. · 2020 [cited by applicant]
US 20200332022A1 · Labrijn et al. · 2020 [cited by applicant]
US 20210070877A1 · Satijn et al. · 2021 [cited by applicant]
US 20210230296A1 · Satijn et al. · 2021 [cited by applicant]
US 20210230301A1 · De Jong et al. · 2021 [cited by applicant]
US 20210292418A1 · Koopman et al. · 2021 [cited by applicant]
US 20220048999A1 · Koopman et al. · 2022 [cited by applicant]
US 20220049013A1 · Satijn et al. · 2022 [cited by applicant]
US 20220324980A1 · Koopman et al. · 2022 [cited by applicant]
US 20220380464A1 · Rademaker et al. · 2022 [cited by applicant]
US 20220389101A1 · Rademaker et al. · 2022 [cited by applicant]
US 20230227495A1 · Gramer et al. · 2023 [cited by applicant]
US 20230322947A1 · Labrijn et al. · 2023 [cited by applicant]
US 20230365714A1 · Koopman et al. · 2023 [cited by applicant]
US 20230374131A1 · Van Den Brink et al. · 2023 [cited by applicant]
US 20240209117A1 · Labrijn et al. · 2024 [cited by applicant]
US 20240392032A1 · Satijn et al. · 2024 [cited by applicant]
CN 102250246A · 2011 [cited by applicant]
EP 0629240A1 · 1994 [cited by applicant]
EP 1870459A1 · 2007 [cited by applicant]
WO 9222653A1 · 1992 [cited by applicant]
WO 9850431A2 · 1998 [cited by applicant]
WO 200046147A2 · 2000 [cited by applicant]
WO 0070087A1 · 2000 [cited by applicant]
WO 2002020039A2 · 2002 [cited by applicant]
WO 2007059782A1 · 2007 [cited by applicant]
WO 2007110205A2 · 2007 [cited by applicant]
WO 2008003116A2 · 2008 [cited by applicant]
WO 2008119567A2 · 2008 [cited by applicant]
WO 2008157379A2 · 2008 [cited by applicant]
WO 2009058383A2 · 2009 [cited by applicant]
WO 2009080254A1 · 2009 [cited by applicant]
WO 2009089004A1 · 2009 [cited by applicant]
WO 2010015792A1 · 2010 [cited by applicant]
WO 2010026923A1 · 2010 [cited by applicant]
WO 2010059315A1 · 2010 [cited by applicant]
WO 2010080538A1 · 2010 [cited by applicant]
WO 2010111625A1 · 2010 [cited by applicant]
WO 2010129304A2 · 2010 [cited by applicant]
WO 2010134666A1 · 2010 [cited by applicant]
WO 2011028952A1 · 2011 [cited by applicant]
WO 2011066501A1 · 2011 [cited by applicant]
WO 2011117329A1 · 2011 [cited by applicant]
WO 2011110642A2 · 2011 [cited by applicant]
WO 2011131746A2 · 2011 [cited by applicant]
WO 2011143545A1 · 2011 [cited by applicant]
WO 2012023053A2 · 2012 [cited by applicant]
WO 2012025525A1 · 2012 [cited by applicant]
WO 2012025530A1 · 2012 [cited by applicant]
WO 2012058768A1 · 2012 [cited by applicant]
WO 2012143524A2 · 2012 [cited by applicant]
WO 2012162067A2 · 2012 [cited by applicant]
WO 2013060867A2 · 2013 [cited by applicant]
WO 2013157953A1 · 2013 [cited by applicant]
WO 2013186613A1 · 2013 [cited by applicant]
WO 2013188693A1 · 2013 [cited by applicant]
WO 2014081202A1 · 2014 [cited by applicant]
WO 2014108483A1 · 2014 [cited by applicant]
WO 2015001085A1 · 2015 [cited by applicant]
Paul, Fundamental Immunology, 3rd Edition, 1993, pp. 292-295, under the heading Fv Structure and Diversity in Three Dimensions (Year: 1993). [cited by examiner]
Casset et al, BBRC 307, 198-205 2003 (Year: 2003). [cited by examiner]
Pascalis et al, The Journal of Immunology vol. 169, 3076-3084, 2002 (Year: 2002). [cited by examiner]
Rudikoff et al, Proc. Natl. Acad. Sci. USA 1982 vol. 79: p. 1979 (Year: 1979). [cited by examiner]
Almagro J. C. et al, “Humanization of Antibodies,” Frontiers in BioScience, vol. 13:1619-1633 (2008). [cited by applicant]
Bokemeyer et al., 2009, J Clin Oncol (Meeting Abstracts), 3036. [cited by applicant]
Bortoletto, N et al. “Optimizing anti-CD3 affinity for effective T cell targeting against tumor cells,” European Journal of Immunology, vol. 32 (11): 3102-3107 (2002). [cited by applicant]
Bostrom, J. et al., “Variants of the Antibody Herceptin That Interact with HER2 and VEGF at the Antigen Binding Site,” Science, vol. 323: 1610-1614 (2009). [cited by applicant]
Casset et al., BBRC, vol. 307:198-205 (2003). [cited by applicant]
Doppalapudi, V.R., et al., “Chemically programmed antibodies: Endothelin receptor targeting CovX-Bodies,” Bioorg. Med. Chem. Lett., vol. 17: 501-506 (2007). [cited by applicant]
Heiss, M. et al., “The trifunctional antibody catumaxomab for the treatment of malignant ascites due to epithelial cancer: results of a prospective randomized phase II/III trial ,” Int J Cancer, vol. 127: 2209-2221 (201… [cited by applicant]
Herold, K. et al., “A Single Course of Anti-CD3 Monoclonal Antibody hOKT3 1(Ala-Ala) Results in Improvement in Peptide Responses and Clinical Parameters for at Least 2 Years after Onset of Type 1 Diabetes,” Diabetes, vo… [cited by applicant]
Himila, I. et al., “A bispecific nanobody to provide full protection against lethal scorpion envenoming ,” FASEB J., vol. 24: 3479-3489 (2010). [cited by applicant]
Hinojosa, L. et al., “Construction of a Recombinant Non-Mitogenic Anti-Human CD3 Antibody,” Hybridoma, vol. 29 (2):115-124 (2010). [cited by applicant]
Jones, K. et al., “Evolving novel anti-HER2 strategies,” Lancet Oncol., vol. 10:1179-1187 (2009). [cited by applicant]
Kiewe, P. et al., “Phase 1 Trial of the Trifunctional Anti-HER2 X Anti-CD3 Antibody Ertumaxomab in Metastatic Breast Cancer” Clinical Cancer Research, vol. 12 (10): 3085-3091 (2006). [cited by applicant]
LaFleur, D. et al., “Monoclonal antibody therapeutics with up to five specificities: functional enhancement through fusion of target-specific peptides,” MAbs, vol. 5(2):208-218 (2013). [cited by applicant]
Lawrence, L. et al., “Orientation of antigen binding sites in dimeric and trimeric single chain Fv antibody fragments,” FEBS Lett., vol. 425(3):479-484 (1998). [cited by applicant]
Lewis' S. et al., “Generation of bispecific igG antibodies by structure-based design of an orthogonal Fab interface,” Nat Biotechnol, vol. 32(2):191-198 (2014). [cited by applicant]
Li, J. J et al.' “Phase I trial of a humanized,Fe receptor nonbinding anti-CD3 antibody, hu12F6mu in patients receiving renal allografts,” MABS, vol. 2(4): 3085-3091 (2010). [cited by applicant]
Linke, R. et al., “Catumaxomab: clinical development and future directions,” MAbs, vol. 2: 129-136 (2010). [cited by applicant]
Lum, L. et al., “Targeting T cells with bispecific antibodies for cancer therapy,” BioDrugs, vol. 25: 365-379 (2011). [cited by applicant]
Molhoj, M. et al., “CD19-/CD3-bispecific antibody of the BITE class is far superior to tandem diabody with respect to redirected tumor cell lysis,” Molecular Immunology, vol. 44(8)3038 (2007). [cited by applicant]
Muller, D. et al., “Bispecific antibodies for cancer immunotherapy: Current perspectives,” BioDrugs, vol. 24: 89-98 (2010). [cited by applicant]
Pascalis et al., The Journal of Immunology, vol. 169, 3076-3084 (2002). [cited by applicant]
Paul, Fundamental Immunology, 3rd Edition, pp. 292-295, under the heading Fv Structure and Diversity in Three Dimensions (1993). [cited by applicant]
Pearce, L et al., “Linear gene fusions of antibody fragments with streptavidin can be linked to biotin labelled secondary molecules to form bispecific reagents,” Biochem Mol Biol Int., vol. 42(6):1179-1188 (1997). [cited by applicant]
Reusch, U. et al., “A travalent bispecific TandAb (CD19/CD3), AFM11, efficiently recruits T cells for the potent lysis of CD19(+) tumor cells,” Mabs, vol. 7(3):584-604 (2015). [cited by applicant]
Reusch, U. et al., “Anti-CD3 x anti-epidermal growth factor receptor (EGFR) bispecific antibody redirects T-cell cytolytic activity to EGFR-positive cancers in vitro and in an animal model,” Clin Cancer Res., vol. 12(1)… [cited by applicant]
Rudikoff et al. (Proc. Natl. Acad. Sci. USA, 79: 1979-1983, Mar. 1982) (Year: 1982. [cited by applicant]
Ruf, P. et al., “Pharmacokinetics, immunogenicity and bioactivity of the therapeutic antibody catumaxomab intraperitoneally administered to cancer patients,” Br J Clin Pharmacol_ vol. 69: 617-625 (2010). [cited by applicant]
Staerz, U. et al., “Hybrid antibodies can target sites for attack by T cells,” Nature, vol. 314:628-631 (1985). [cited by applicant]
Vidarsson, G et al, “igG Subclasses and Allotypes: from structure to Effector Functions”, Frontiers in Immunology, vol. 5, 2014, 1-17. [cited by applicant]
Viola, k et al., “T cell activation determined by T cell receptor No. and tunable thresholds,” Science, vol. 273 (5271) 104-106 (1996). [cited by applicant]
Webster, D. et al., “Engineering antibody affinity and specificity,” Int J Cancer Suppl., vol. 3:13-16 (1998). [cited by applicant]
Wu et al., 2010, Generation and Characterization of a Dual Variable Domain Immunoglobulin (DVD-IgIN) Molecule, In Antibody Engineering, Springer Berlin Heidelberg, 8 pages. [cited by applicant]
Xu, D. et al., “In vitro characterization of five humanized OKT3 effector function variant antibodies,” Cell Immunol., vol. 200(1):16-26 (2000). [cited by applicant]
Zhu X. et al., “COMBODY: one-domain antibody multimer with improved avidity,” Immunol Cell Biol., vol. 88 (6):667-75 (2010). [cited by applicant]
Ausubel, F. et al., ed. Current Protocols in Molecular Biology, Greene Publishing and Wiley InterScience New York (1987). [cited by applicant]
Barbas, C. et al., “Molecular Profile of an Antibody Response to HIV-1 as Probed by Combinatorial Libraries,” J. Mol. Biol., vol. 230(3): 812-823 (1993). [cited by applicant]
Benvenisty, N. et al., “Direct introduction of genes into rats and expression of the genes,” PNAS, vol. 83:9551-9555 (1986). [cited by applicant]
Bird, R.E. et al., “Single-chain antigen-binding proteins,” Science, vol. 242(4877):423-426 (1988). [cited by applicant]
Bitter, G.A., et al., “Expression and secretion vectors for yeast,” Methods in Enzymol., vol. 153: 516-544 (1987). [cited by applicant]
Blankenship J. et al., “Abstract #5465: CD79BxDR SCORPIONTM molecule: a single chain, bispecific immunotherapeutic with potent in vitro activity against B cell lymphoma ,” AACR 100th Annual Meeting, Cancer Res/, vol. 69… [cited by applicant]
Bostrom et al., “High Affinity Antigen Recognition of the Dual Specific Variants of Herceptin Is Entropy-Driven in Spite of Structural Plasticity,” PLOS One, vol. 6(4): 1-12 (2011). [cited by applicant]
Brochet X., “IMGT/V-Quest: the highly customized and integrated system for IG and TR standardized V-J and V-D-J sequence analysis,” Nucl Acids Res., vol. 36:W503-508 (2008). [cited by applicant]
Brown, JM, Clinical use of monoclonal antibodies, pp. 227-249—Book, 1993, Chapman and Hall. [cited by applicant]
Bruhns, P. et al., “Specificity and affinity of human Fcy gamma receptors and their polymorphic variants for human IgG subclasses,” Blood, vol. 113(16): 3716-3725 (2009). [cited by applicant]
Bryson, C. et al., “Prediction of immunogenicity of therapeutic proteins: validity of computational tools,” Biodrugs, vol. 24 (1): 1-8, (2010). [cited by applicant]
Canfield, S.M. et al., “The Binding Affinity of Human IgG for its High Affinity Fc Receptor Is Determined by Multiple Amino Acids in the CH2 Domain and Is Modulated by the Hinge Region,” J. Exp. Med., vol. 173:1483-1491… [cited by applicant]
Corsaro, C.M et al., “Enhancing the efficiency of DNA-mediated gene transfer in mammalian cells,” Somatic Cell Genetics, vol. 7(5):603-615 (1981). [cited by applicant]
Dall'Acqua, W.F. et al., “Modulation of the Effector Functions of a Human IgG1 through Engineering of Its Hinge Region,” The Journal of Immunology, vol. 177(2):1129-1138 (2006). [cited by applicant]
De Pascalis, R. et al., “Grafting of “abbreviated” complementarity-determining regions containing specificity-determining residues essential for ligand contact to engineer a less immunogenic humanized monoclonal antibod… [cited by applicant]
Dimasi N, et al., “The design and characterization of oligospecific antibodies for simultaneous targeting of multiple disease mediators,” J Mol Biol., vol. 393(3):672-92 (2009). [cited by applicant]
Duncan, A.R et al., “The Binding Site for Clq on IgG,” Nature, vol. 332: 738-740 (1988). [cited by applicant]
Giudicelli, V., et al., “IMGT/V-QUEST: IMGT Standardized Analysis of the Immunoglobulin (IG) and T Cell Receptor (TR) Nucleotide Sequences,” Cold Spring Harbor Protocols, vol. 2011(6):695-716 (2011). [cited by applicant]
Haber et al., “GGeneration of T-cell-redirecting bispecific antibodies with differentiated profiles of cytokine release and biodistribution by CD3 affinity tuning” Scientific Reports, vol. 11:1-17 (2021). [cited by applicant]
Idusogie EE, et al., “Mapping of the C1q binding site on rituxan, a chimeric antibody with a human IgG1 Fc,” J Immunol.,, vol. 164(8): 4178-4184(2000). [cited by applicant]
Jing, Li, et al., “Phase I trial of a humanized, Fe receptor nonbinding anti-CD3 antibody, hu12F6mu in patients receiving renal allografts,” MABS, vol. 2(4): 449-456 (2010). [cited by applicant]
Kabat et al., Sequences of Proteins of Immunological Interest, Fifth Edition. 1991 NIH Publication No. 91-3242. [cited by applicant]
Leabman M. et al., “Effects of altered FcγR binding on antibody pharmacokinetics in cynomolgus monkeys,” Mabs, vol. 5(6):896-903 (2013). [cited by applicant]
Lefranc MP, et al., “IMGT, the international ImMunoGeneTics database.,” Nucleic Acids Res., vol. 27(1):209-212 (1999). [cited by applicant]
Lightle S, et al., “Mutations within a human IgG2 antibody form distinct and homogeneous disulfide isomers but do not affect Fc gamma receptor or C1q binding” Protein Sci., vol. 19(4):753-62 (2010). [cited by applicant]
Myers EW et al., “Optimal alignments in linear space,” CABIOS, vol. 4(1):11-17 (1988). [cited by applicant]
Needleman and Wunsch, J., “A general method applicable to the search for similarities in the amino acid sequence of two proteins,” J. Mol. Biol., vol. 48(3) 443-453 (1970). [cited by applicant]
Oganesyan, V. et al., “Structural characterization of a human Fc fragment engineered for lack of effector functions,” Acta Crystallographica, D64:700-704 (2008). [cited by applicant]
Parren PW, et al., “On the interaction of IgG subclasses with the low affinity Fc gamma RIIa (CD32) on human monocytes, neutrophils, and platelets, Analysis of a functional polymorphism to human IgG2,” J Clin Invest., v… [cited by applicant]
Paul, W, Fundamental Immunology, 2nd Edition, Raven Press, Chapter 12, 332-337 (1989). [cited by applicant]
Perry, L.C. et al., “New approaches to prediction of immune responses to therapeutic proteins during preclinical development,” Drugs in R&D, vol. 9(6): 385-396 (2008). [cited by applicant]
Remington, Medical Applications of Radioisotopes, 18 Ed., pp. 624-652—Book, 1990, Mack Publishing Co., Gennaro. [cited by applicant]
Remington: The Science and Practice of Pharmacy, 19th Edition, Gennaro, Ed., Mack Publishing Co., Easton, PA, 1995. [cited by applicant]
Ritter, G. et al., “Serological analysis of human anti-human antibody responses in colon cancer patients treated with repeated doses of humanized monoclonal antibody A33,” Cancer Research, vol. 61(18): 6851-6859 (2001). [cited by applicant]
Robinson, J.R., “Sustained and controlled release drug delivery systems,” Book, Marcel Dekker (1978). [cited by applicant]
Sambrook et al., “Molecular Cloning: A laboratory Manual,” New York: Cold Spring Harbor Laboratory Press, Ch. 15, Second edition, , pp. 2.43-2.84 (1989). [cited by applicant]
Schakowski F, et al., “A novel minimal-size vector (MIDGE) improves transgene expression in colon carcinoma cells and avoids transfection of undesired DNA,” Mol Ther., vol. 3(5 Pt 1):793-800 (2001). [cited by applicant]
Shields, R. L. et al., “High Resolution Mapping of the Binding Site on Human IgG1 for FcyRI, FcyRII, FCyRIII and FcyR and Design of IgG1 Variants with Improved Binding to the FcgR*, ” The Journal of Biological Chemistry… [cited by applicant]
Sleebom et al., “MDA-MB-231 Breast Cancer Cells and Their CSC Population Migrate Towards Low Oxygen in a Microfluidic Gradient Device,” International Journal of Molecular Sciences, vol. 19 (3047)1-15 (2018). [cited by applicant]
Sykes KF, et al., “Linear expression elements: a rapid, in vivo, method to screen for gene functions,” Nat Biotechnol., vol. 17(4):355-9 (1999). [cited by applicant]
T cell Epitope Database, www.IEDB.org, 1 page (2024). [cited by applicant]
Thompson et al., “CLUSTAL W: improving the sensitivity of progressive multiple sequence alignment through sequence weighting, position-specific gap penalties and weight matrix choice”, Nucleic Acids Rest., vol. 22(22): … [cited by applicant]
Van Heeke G, et al. “Expression of human asparagine synthetase in [cited by applicant]
Welch et al., “Potential Labeling of Monoclonal Antibodies With Positron Emitters,” Srivastava, Plenum Press (1988). [cited by applicant]
Wigler M., et al. “Biochemical transfer of single-copy eucaryotic genes using total cellular DNA as donor,” Cell, vol. 14 (3):725-31 (1978). [cited by applicant]
Wranik BJ et al., “LUZ-Y, a novel platform for the mammalian cell production of full-length IgG-bispecific antibodies,” J Biol Chem., vol. 287(52):43331-9 (2012). [cited by applicant]
Zheng, L., et al., “Expression Improvement and Mechanistic Study of the Retro-Diels-Alderase Catalytic Antibody 10F11 by Site-directed Mutagenesis,” Journal of Molecular Biology, vol. 341(3), 807-14 (2004). [cited by applicant]
U.S. Appl. No. 17/939,736, filed Sep. 7, 2022, Michael Gramer. [cited by applicant]
Huston, J. et al., “Protein engineering of antibody binding sites: recovery of specific activity in an anti-digoxin single-chain Fv analogue produced in [cited by applicant]