Reprogramming the Constant Region of Immunoglobulin G Subclasses for Enhanced Therapeutic Potency Against Cancer

Overview

Journal Biomolecules

Publisher MDPI

Specialties Biochemistry
Molecular Biology

Date 2020 Mar 4

PMID 32121592

Citations 4

Authors

Tae Hyun Kang

Sang Taek Jung

Affiliations

Soon will be listed here.

Abstract

The constant region of immunoglobulin (Ig) G antibodies is responsible for their effector immune mechanism and prolongs serum half-life, while the fragment variable (Fv) region is responsible for cellular or tissue targeting. Therefore, antibody engineering for cancer therapeutics focuses on both functional efficacy of the constant region and tissue- or cell-specificity of the Fv region. In the functional aspect of therapeutic purposes, antibody engineers in both academia and industry have capitalized on the constant region of different IgG subclasses and engineered the constant region to enhance therapeutic efficacy against cancer, leading to a number of successes for cancer patients in clinical settings. In this article, we review IgG subclasses for cancer therapeutics, including i) IgG1, ii) IgG2, 3, and 4, iii) recent findings on Fc receptor functions, and iv) future directions of reprogramming the constant region of IgG to maximize the efficacy of antibody drug molecules in cancer patients.

Citing Articles

Editorial: Progress and challenges in computational structure-based design and development of biologic drugs.

Sulea T, Kumar S, Kuroda D Front Mol Biosci. 2024; 11:1360267.

PMID: 38389897 PMC: 10883042. DOI: 10.3389/fmolb.2024.1360267.

Promising Highly Targeted Therapies for Cholangiocarcinoma: A Review and Future Perspectives.

Kuwatani M, Sakamoto N Cancers (Basel). 2023; 15(14).

PMID: 37509347 PMC: 10378186. DOI: 10.3390/cancers15143686.

Fc Receptor Variants and Disease: A Crucial Factor to Consider in the Antibody Therapeutics in Clinic.

Kim J, Lee J, Kim H, Kwak M, Kang T Int J Mol Sci. 2021; 22(17).

PMID: 34502398 PMC: 8431278. DOI: 10.3390/ijms22179489.

Solubility, Stability, and Avidity of Recombinant Antibody Fragments Expressed in Microorganisms.

Kang T, Seong B Front Microbiol. 2020; 11:1927.

PMID: 33101218 PMC: 7546209. DOI: 10.3389/fmicb.2020.01927.

References

Clynes R, Towers T, Presta L, Ravetch J . Inhibitory Fc receptors modulate in vivo cytotoxicity against tumor targets. Nat Med. 2000; 6(4):443-6. DOI: 10.1038/74704. View

Rogers K, Huang Y, Ruppert A, Awan F, Heerema N, Hoffman C . Phase 1b study of obinutuzumab, ibrutinib, and venetoclax in relapsed and refractory chronic lymphocytic leukemia. Blood. 2018; 132(15):1568-1572. PMC: 6182267. DOI: 10.1182/blood-2018-05-853564. View

Dahan R, Sega E, Engelhardt J, Selby M, Korman A, Ravetch J . FcγRs Modulate the Anti-tumor Activity of Antibodies Targeting the PD-1/PD-L1 Axis. Cancer Cell. 2015; 28(3):285-95. DOI: 10.1016/j.ccell.2015.08.004. View

Kontermann R, Brinkmann U . Bispecific antibodies. Drug Discov Today. 2015; 20(7):838-47. DOI: 10.1016/j.drudis.2015.02.008. View

Hatjiharissi E, Xu L, Santos D, Hunter Z, Ciccarelli B, Verselis S . Increased natural killer cell expression of CD16, augmented binding and ADCC activity to rituximab among individuals expressing the Fc{gamma}RIIIa-158 V/V and V/F polymorphism. Blood. 2007; 110(7):2561-4. PMC: 1988936. DOI: 10.1182/blood-2007-01-070656. View

Shields R, Lai J, Keck R, OConnell L, Hong K, Meng Y . Lack of fucose on human IgG1 N-linked oligosaccharide improves binding to human Fcgamma RIII and antibody-dependent cellular toxicity. J Biol Chem. 2002; 277(30):26733-40. DOI: 10.1074/jbc.M202069200. View

Sharma P, Hu-Lieskovan S, Wargo J, Ribas A . Primary, Adaptive, and Acquired Resistance to Cancer Immunotherapy. Cell. 2017; 168(4):707-723. PMC: 5391692. DOI: 10.1016/j.cell.2017.01.017. View

Lim S, Vaughan A, Ashton-Key M, Williams E, Dixon S, Chan H . Fc gamma receptor IIb on target B cells promotes rituximab internalization and reduces clinical efficacy. Blood. 2011; 118(9):2530-40. DOI: 10.1182/blood-2011-01-330357. View

Schneider-Merck T, Lammerts van Bueren J, Berger S, Rossen K, van Berkel P, Derer S . Human IgG2 antibodies against epidermal growth factor receptor effectively trigger antibody-dependent cellular cytotoxicity but, in contrast to IgG1, only by cells of myeloid lineage. J Immunol. 2009; 184(1):512-20. DOI: 10.4049/jimmunol.0900847. View

10.

Brezski R, Kinder M, Grugan K, Soring K, Carton J, Greenplate A . A monoclonal antibody against hinge-cleaved IgG restores effector function to proteolytically-inactivated IgGs in vitro and in vivo. MAbs. 2014; 6(5):1265-73. PMC: 4623506. DOI: 10.4161/mabs.29825. View

11.

Engblom C, Pfirschke C, Pittet M . The role of myeloid cells in cancer therapies. Nat Rev Cancer. 2016; 16(7):447-62. DOI: 10.1038/nrc.2016.54. View

12.

Cassel D, Keller M, Surrey S, Schwartz E, Schreiber A, Rappaport E . Differential expression of Fc gamma RIIA, Fc gamma RIIB and Fc gamma RIIC in hematopoietic cells: analysis of transcripts. Mol Immunol. 1993; 30(5):451-60. DOI: 10.1016/0161-5890(93)90113-p. View

13.

Capuano C, Pighi C, Molfetta R, Paolini R, Battella S, Palmieri G . Obinutuzumab-mediated high-affinity ligation of FcγRIIIA/CD16 primes NK cells for IFNγ production. Oncoimmunology. 2017; 6(3):e1290037. PMC: 5384385. DOI: 10.1080/2162402X.2017.1290037. View

14.

Beutier H, Hechler B, Godon O, Wang Y, Gillis C, de Chaisemartin L . Platelets expressing IgG receptor FcγRIIA/CD32A determine the severity of experimental anaphylaxis. Sci Immunol. 2018; 3(22). DOI: 10.1126/sciimmunol.aan5997. View

15.

Oganesyan V, Damschroder M, Leach W, Wu H, DallAcqua W . Structural characterization of a mutated, ADCC-enhanced human Fc fragment. Mol Immunol. 2007; 45(7):1872-82. DOI: 10.1016/j.molimm.2007.10.042. View

16.

Oflazoglu E, Stone I, Brown L, Gordon K, van Rooijen N, Jonas M . Macrophages and Fc-receptor interactions contribute to the antitumour activities of the anti-CD40 antibody SGN-40. Br J Cancer. 2008; 100(1):113-7. PMC: 2634668. DOI: 10.1038/sj.bjc.6604812. View

17.

Cohen-Solal J, Cassard L, Fridman W, Sautes-Fridman C . Fc gamma receptors. Immunol Lett. 2004; 92(3):199-205. DOI: 10.1016/j.imlet.2004.01.012. View

18.

Zhang D, Goldberg M, Chiu M . Fc Engineering Approaches to Enhance the Agonism and Effector Functions of an Anti-OX40 Antibody. J Biol Chem. 2016; 291(53):27134-27146. PMC: 5207143. DOI: 10.1074/jbc.M116.757773. View

19.

Aalberse R, Schuurman J . IgG4 breaking the rules. Immunology. 2002; 105(1):9-19. PMC: 1782638. DOI: 10.1046/j.0019-2805.2001.01341.x. View

20.

Angal S, King D, Bodmer M, Turner A, Lawson A, Roberts G . A single amino acid substitution abolishes the heterogeneity of chimeric mouse/human (IgG4) antibody. Mol Immunol. 1993; 30(1):105-8. DOI: 10.1016/0161-5890(93)90432-b. View