New Generations of Antibodies and Scaffold Proteins as a Way to Create Highly Selective Conjugates for Oncology

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Published: Mar 24, 2026
DOI: https://doi.org/10.18097/BMCRM00305
Keywords:
antibody-drug conjugates (ADC); targeted therapy; bispecific antibodies; small scaffold proteins; linkers; cytotoxic agents; site-specific conjugation; PROTAC

Main Article Content

I.V. Shulcheva
Institute of Biological Instrumentation, Federal Research Center “Pushchino Scientific Center for Biological Research” of the Russian Academy of Sciences, 142290, Russian Federation, Moscow Region, Pushchino, Institutskaya St., 7
A.B. Ulitin
Institute of Biological Instrumentation, Federal Research Center “Pushchino Scientific Center for Biological Research” of the Russian Academy of Sciences, 142290, Russian Federation, Moscow Region, Pushchino, Institutskaya St., 7

Abstract

This review provides a systematic analysis of modern strategies for developing highly selective therapeutic conjugates for oncology. It examines the evolution from first-generation antibody-drug conjugates (ADCs) to advanced next-generation platforms. The focus is on key conjugate components: targeting modules (bispecific antibodies, small scaffold proteins — affibodies, DARPins, adnectins), linker systems with controlled release, and an expanding arsenal of cytotoxic and cytomodulatory payloads. Special attention is given to innovative technologies, such as PROTAC-ADCs, oligonucleotide conjugates, and photoimmunoconjugates, which enable targeting of "undruggable" molecules and manipulation of intracellular processes. Strategies for site-specific conjugation to obtain homogeneous preparations are analyzed. The conclusion is drawn that the convergence of refined components and novel platforms shapes the future of targeted therapy, aimed significantly at enhancing the therapeutic index and overcoming drug resistance.

Article Details

How to Cite
Shulcheva, I., & Ulitin, A. (2026). New Generations of Antibodies and Scaffold Proteins as a Way to Create Highly Selective Conjugates for Oncology. Biomedical Chemistry: Research and Methods, 9(1), e00305. https://doi.org/10.18097/BMCRM00305
Issue
Vol. 9 No. 1 (2026): Online first
Section
REVIEWS

References

  1. Anderl, J., Faulstich, H., Hechler, T., and Kulke, M. (2013) Antibody-drug conjugate payloads. Methods in Molecular Biology, 1045, 51–70. DOI
  2. Fu, Z., Li, S., Han, S., Shi, C., and Zhang, Y. (2022) Antibody drug conjugate: the «biological missile» for targeted cancer therapy. Signal Transduction and Targeted Therapy, 7(1), 93. DOI
  3. Haque, M., Forte, N., and Baker, J.R. (2021) Site-selective lysine conjugation methods and applications towards antibody-drug conjugates. Chemical Communications, 57(82), 10689–10702. DOI
  4. Beck, A., Goetsch, L., Dumontet, C., and Corvaïa, N. (2017) Strategies and challenges for the next generation of antibody–drug conjugates. Nature Reviews Drug Discovery, 16(5), 315–337. DOI
  5. Miao, Z., Levi, J., and Cheng, Z. (2011) Protein scaffold-based molecular probes for cancer molecular imaging. Amino Acids, 41(5), 1037–1047. DOI
  6. Puthenveetil, S., Loganzo, F., He, H., Dirico, K., Green, M., Teske, J., Musto, S., Clark, T., Rago, B., Koehn, F., et al. (2016) Natural product splicing inhibitors: a new class of antibody-drug conjugate (ADC) payloads. Bioconjugate Chemistry, 27(8), 1880–1888. DOI
  7. Wang, R., Hu, B., Pan, Z., Mo, C., Zhao, X., Liu, G., Hou, P., Cui, Q., Xu, Z., Wang, W., et al. (2025) Antibody-drug conjugates (ADCs): current and future biopharmaceuticals. Journal of Hematology & Oncology, 18, 51. DOI
  8. Chen, B., Zheng, X., Wu, J., Chen, G., Yu, J., Xu, Y., Wu, W.K.K., Tse, G.M.K., To, K.F., and Kang, W. (2025) Antibody-drug conjugates in cancer therapy: current landscape, challenges, and future directions. Molecular Cancer, 24(1), 279. DOI
  9. U.S. Food and Drug Administration. Brentuximab vedotin (marketed as Adcetris) Information. Retrieved December 1, 2025, from: https://www.fda.gov/drugs/postmarket-drug-safety-information-patients-and-providers/brentuximabvedotin-marketed-adcetris-information
  10. U.S. Food and Drug Administration. ADCETRIS (brentuximab vedotin) label. Retrieved December 1, 2025, from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/125427s105lbl.pdf
  11. U.S. Food and Drug Administration. BESPONSA (inotuzumab ozogamicin) label. Retrieved December 1, 2025 , from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/761040s000lbl.pdf
  12. U.S. Food and Drug Administration. FDA approves gemtuzumab ozogamicin for CD33-positive AML. Retrieved December 1, 2025, from: https://www.fda.gov/drugs/resources-information-approved-drugs/fdaapproves-gemtuzumab-ozogamicin-cd33-positive-aml
  13. U.S. Food and Drug Administration. FDA approves moxetumomab pasudotox-tdfk for hairy cell leukemia. Retrieved December 1, 2025, from: https://www.fda.gov/drugs/resources-information-approved-drugs/fdaapproves-moxetumomab-pasudotox-tdfk-hairy-cell-leukemia
  14. U.S. Food and Drug Administration. FDA approves polatuzumab vedotinpiiq for previously untreated diffuse large B-cell lymphoma, not otherwise specified. Retrieved December 1, 2025, from: https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-polatuzumab-vedotin-piiqpreviously-untreated-diffuse-large-b-cell-lymphoma-not
  15. U.S. Food and Drug Administration. FDA DISCO Burst Edition: Approval of Padcev (enfortumab vedotin-ejfv) for locally advanced or metastatic urothelial cancer. Retrieved December 1, 2025, from: https://www.fda.gov/drugs/resources-information-approved-drugs/fda-disco-burst-edition-approvalpadcev-enfortumab-vedotin-ejfv-locally-advanced-or-metastatic
  16. U.S. Food and Drug Administration. FDA DISCO Burst Edition: FDA approval of Enhertu (fam-trastuzumab deruxtecan-nxki) for adult patients with unresectable or metastatic HER2-positive breast cancer. Retrieved December 1, 2025, from: https://www.fda.gov/drugs/resources-information-approved-drugs/fda-disco-burst-edition-fda-approval-enhertu-fam-trastuzumab-deruxtecan-nxkiadult-patients
  17. U.S. Food and Drug Administration. FDA grants regular approval to sacituzumab govitecan for triple-negative breast cancer. , from: https://www.fda. gov/drugs/resources-information-approved-drugs/fda-grants-regular-approvalsacituzumab- govitecan-triple-negative-breast-cancer
  18. U.S. Food and Drug Administration. FDA approves belantamab mafodotinblmf for relapsed or refractory multiple myeloma. , from: https://www.fda. gov/drugs/resources-information-approved-drugs/fda-approves-belantamabmafodotin- blmf-relapsed-or-refractory-multiple-myeloma
  19. U.S. Food and Drug Administration. FDA DISCO Burst Edition: FDA approvals of Jemperli (dostarlimab-gxly) for adults with mismatch repair deficient solid tumors. Retrieved December 1, 2025, from: https://www.fda. gov/drugs/resources-information-approved-drugs/fda-disco-burst-edition-fdaapprovals- jemperli-dostarlimab-gxly-adults-mismatch-repair-deficient
  20. U.S. Food and Drug Administration. FDA approves tisotumab vedotintftv for recurrent or metastatic cervical cancer. Retrieved December 1, 2025, from: https://www.fda.gov/drugs/resources-information-approved-drugs/fdaapproves- tisotumab-vedotin-tftv-recurrent-or-metastatic-cervical-cancer
  21. Drug Delivery System, Retrieved December 1, 2025, from: https://www. jstage.jst.go.jp/article/dds/40/3/40_216/_article/-char/en
  22. U.S. Food and Drug Administration. FDA DISCO Burst Edition: FDA approval of ELAHERE (mirvetuximab soravtansine-gynx) for FRα-positive, platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer. Retrieved December 1, 2025, from: https://www.fda.gov/drugs/ resources-information-approved-drugs/fda-disco-burst-edition-fda-approvalelahere- mirvetuximab-soravtansine-gynx-fra-positive-platinum
  23. U.S. Food and Drug Administration. FDA approves zolbetuximab (Clzb) with chemotherapy for gastric or gastroesophageal junction adenocarcinoma. Retrieved December 1, 2025, from: https://www.fda.gov/drugs/resourcesinformation- approved-drugs/fda-approves-zolbetuximab-clzb-chemotherapygastric- or-gastroesophageal-junction-adenocarcinoma
  24. Hemonc.org. Disitamab vedotin (Aidixi). Retrieved December 1, 2025, from: https://hemonc.org/wiki/Disitamab_vedotin_(Aidixi)
  25. Bakhtiar, R. (2016) Antibody drug conjugates. Biotechnology Letters, 38(10), 1655–1664. DOI
  26. Birrer, M.J., Moore, K.N., Betella, I., and Bates, R.C. (2019) Antibodydrug conjugate-based therapeutics: state of the science. Journal of the National Cancer Institute, 111(6), 538–549. DOI
  27. Natsume, A., Niwa, R., and Satoh, M. (2009) Improving effector functions of antibodies for cancer treatment: enhancing ADCC and CDC. Drug Design, Development and Therapy, 3, 7-16.
  28. Radocha, J., van de Donk, N.W.C.J., and Weisel, K. (2021) Monoclonal antibodies and antibody drug conjugates in multiple myeloma. Cancers, 13(7), 1571. DOI
  29. Oostra, D.R., and Macrae, E.R. (2014) Role of trastuzumab emtansine in the treatment of HER2-positive breast cancer. Breast Cancer: Targets and Therapy, 6, 103–113. DOI
  30. Damelin, M., Zhong, W., Myers, J., and Sapra, P. (2015) Evolving strategies for target selection for antibody-drug conjugates. Pharmaceutical Research, 32(11), 3494–3507. DOI
  31. Ritchie, M., Tchistiakova, L., and Scott, N. (2012) Implications of receptormediated endocytosis and intracellular trafficking dynamics in the development of antibody drug conjugates. MAbs, 5(1), 13–21. DOI
  32. Donaghy, H. (2016) Effects of antibody, drug and linker on the preclinical and clinical toxicities of antibody-drug conjugates. MAbs, 8(4), 659–671. DOI
  33. de Cecco, M., Galbraith, D.N., and McDermott, L.L. (2021) What makes a good antibody-drug conjugate? Expert Opinion on Biological Therapy, 21(7), 841–847. DOI
  34. Peters, C., and Brown, S. (2015) Antibody-drug conjugates as novel anticancer chemotherapeutics. Bioscience Reports, 35(4), e00225. DOI
  35. Dudley, A.C. (2012) Tumor endothelial cells. Cold Spring Harbor Perspectives in Medicine, 2(3), a006536. DOI
  36. Lu, J., Jiang, F., Lu, A., and Zhang, G. (2016) Linkers having a crucial role in antibody-drug conjugates. International Journal of Molecular Sciences, 17(4), 561. DOI
  37. Fu, Z., Li, S., Han, S., Shi, C., and Zhang, Y. (2022) Antibody drug conjugate: the «biological missile» for targeted cancer therapy. Signal Transduction and Targeted Therapy, 7(1), 93. DOI
  38. Zhang, D., Fourie-O’Donohue, A., Dragovich, P.S., Pillow, T.H., Sadowsky, J.D., Kozak, K.R., Cass, R.T., Liu, L., Deng, Y., Liu, Y., Hop, C.E.C.A., and Khojasteh, S.C. (2019) Catalytic cleavage of disulfide bonds in small molecules and linkers of antibody–drug conjugates. Drug Metabolism and Disposition, 47(10), 1156–1163. DOI
  39. Gondi, C.S., and Rao, J.S. (2013) Cathepsin B as a cancer target. Expert Opinion on Therapeutic Targets, 17(3), 281–291. DOI
  40. Kovtun, Y.V., Audette, C.A., Ye, Y., Xie, H., Ruberti, M.F., Phinney, S.J., Leece, B.A., Chittenden, T., Blättler, W.A., and Goldmacher, V.S. (2006) Antibody-drug conjugates designed to eradicate tumors with homogeneous and heterogeneous expression of the target antigen. Cancer Research, 66(6), 3214–3221. DOI
  41. Puthenveetil, S., Loganzo, F., He, H., Dirico, K., Green, M., Teske, J., Musto, S., Clark, T., Rago, B., Koehn, F., et al. (2016) Natural product splicing inhibitors: a new class of antibody-drug conjugate (ADC) payloads. Bioconjugate Chemistry, 27(8), 1880–1888. DOI
  42. Staudacher, A.H., and Brown, M.P. (2017) Antibody drug conjugates and bystander killing: is antigen-dependent internalisation required? British Journal of Cancer, 117(12), 1736–1742. DOI
  43. Zhao, P., Zhang, Y., Li, W., Jeanty, C., Xiang, G., and Dong, Y. (2020) Recent advances of antibody drug conjugates for clinical applications. Acta Pharmaceutica Sinica B, 10(9), 1589–1600. DOI
  44. Chen, H., Lin, Z., Arnst, K.E., Miller, D.D., and Li, W. (2017) Tubulin inhibitor-based antibody-drug conjugates for cancer therapy. Molecules, 22(8), 1281. DOI
  45. Anderl, J., Faulstich, H., Hechler, T., and Kulke, M. (2013) Antibody-drug conjugate payloads. Methods in Molecular Biology, 1045, 51–70. DOI
  46. Yaghoubi, S., Karimi, M.H., Lotfinia, M., Gharibi, T., Mahi-Birjand, M., Kavi, E., Hosseini, F., Sineh Sepehr, K., Khatami, M., Bagheri, N., and Abdollahpour-Alitappeh, M. (2019) Potential drugs used in the antibodydrug conjugate (ADC) architecture for cancer therapy. Journal of Cellular Physiology, 235(1), 31–64. DOI
  47. Matsuda, Y., and Mendelsohn, B.A. (2020) An overview of process development for antibody-drug conjugates produced by chemical conjugation technology. Expert Opinion on Biological Therapy, 21(7), 963–975. DOI
  48. D’Amico, L., Menzel, U., Prummer, M., Müller, P., Buchi, M., Kashyap, A., Haessler, U., Yermanos, A., Gébleux, R., Briendl, M., Hell, T., Wolter, F.I., Beerli, R.R., Truxova, I., Radek, Š., Vlajnic, T., Grawunder, U., Reddy, S., and Zippelius, A. (2019) A novel anti-HER2 anthracycline-based antibody-drug conjugate induces adaptive anti-tumor immunity and potentiates PD-1 blockade in breast cancer. Journal for ImmunoTherapy of Cancer, 7(1), 16. DOI
  49. Li, Z.N., and Luo, Y. (2023) HSP90 inhibitors and cancer: prospects for use in targeted therapies (Review). Oncology Reports, 49(1), 6. DOI
  50. Sun, Y., Yu, X., Wang, X., Yuan, K., Wang, G., Hu, L., Zhang, G., Pei, W., Wang, L., Sun, C., and Yang, P. (2023) Bispecific antibodies in cancer therapy: target selection and regulatory requirements. Acta Pharmaceutica Sinica B, 13(9), 3583–3597. DOI
  51. Wang, S., Chen, K., Lei, Q., Ma, P., Yuan, A.Q., Zhao, Y., Jiang, Y., Fang, H., Xing, S., Fang, Y., Jiang, N., Miao, H., Zhang, M., Sun, S., Yu, Z., Tao, W., Zhu, Q., Nie, Y., and Li, N. (2021) The state of the art of bispecific antibodies for treating human malignancies. EMBO Molecular Medicine, 13(9), e14291. DOI
  52. Suurs, F.V., Lub-de Hooge, M.N., de Vries, E.G.E., and de Groot, D.J.A. (2019) A review of bispecific antibodies and antibody constructs in oncology and clinical challenges. Pharmacology & Therapeutics, 201, 103–119. DOI
  53. Wang, S., Chen, K., Lei, Q., Ma, P., Yuan, A.Q., Zhao, Y., Jiang, Y., Fang, H., Xing, S., Fang, Y., Jiang, N., Miao, H., Zhang, M., Sun, S., Yu, Z., Tao, W., Zhu, Q., Nie, Y., and Li, N. (2021) The state of the art of bispecific antibodies for treating human malignancies. EMBO Molecular Medicine, 13(9), e14291. DOI
  54. Kang, J., Sun, T., and Zhang, Y. (2022) Immunotherapeutic progress and application of bispecific antibody in cancer. Frontiers in Immunology, 13, 1020003. DOI
  55. Kaplon, H., Crescioli, S., Chenoweth, A., Visweswaraiah, J., and Reichert, J.M. (2023) Antibodies to watch in 2023. MAbs, 15(1), 2153410. DOI
  56. Sheridan, C. (2021) Bispecific antibodies poised to deliver wave of cancer therapies. Nature Biotechnology, 39(3), 251–254. DOI
  57. Yao, Y., Hu, Y., and Wang, F. (2023) Trispecific antibodies for cancer immunotherapy. Immunology, 169(4), 389–399. DOI
  58. Lu, C., Zou, L., Wang, Q., Sun, M., Shi, T., Xu, S., Meng, F., Du, J. (2024) Potent antitumor activity of a bispecific T-cell engager antibody targeting the intracellular antigen KRAS G12V. Biomolecules and Biomedicine, 24(5), 1424- 1434. DOI
  59. U.S. Food and Drug Administration. Pediatric Oncology Drug Approvals. Retrieved December 1, 2025, from: https://www.fda.gov/about-fda/oncologycenter-excellence/pediatric-oncology-drug-approvals
  60. U.S. Food and Drug Administration. FDA grants traditional approval to tarlatamab-dlle for extensive stage small cell lung cancer, Retrieved December 1, 2025, from: https://www.fda.gov/drugs/resources-information-approveddrugs/fda-grants-traditional-approval-tarlatamab-dlle-extensive-stage-smallcell-lung-cancer
  61. U.S. Food and Drug Administration. FDA approves amivantamab-vmjw in combination with carboplatin and pemetrexed for non-small cell lung cancer with EGFR exon 19 deletions or exon 21 L858R mutations. Retrieved December 1, 2025, from: https://www.fda.gov/drugs/resources-informationapproved-drugs/fda-approves-amivantamab-vmjw-carboplatin-and-pemetrexednon-small-cell-lung-cancer-egfr-exon-19
  62. U.S. Food and Drug Administration. FDA DISCO Burst Edition: FDA approvals of Imjudo (tremelimumab) in combination with durvalumab for unresectable hepatocellular carcinoma. Retrieved December 1, 2025, from: https://www.fda.gov/drugs/resources-information-approveddrugs/ fda-disco-burst-edition-fda-approvals-imjudo-tremelimumabcombination- durvalumab-unresectable
  63. U.S. Food and Drug Administration. FDA DISCO Burst Edition: FDA approval of Lunsumio (mosunetuzumab-axgb) for adult patients with relapsed or refractory follicular lymphoma. Retrieved December 1, 2025, from: https:// www.fda.gov/drugs/resources-information-approved-drugs/fda-disco-burstedition- fda-approval-lunsumio-mosunetuzumab-axgb-adult-patients-relapsed-or
  64. U.S. Food and Drug Administration. FDA grants accelerated approval to glofitamab-gxbm for selected relapsed or refractory large B-cell lymphomas. , from: https://www.fda.gov/drugs/drug-approvals-and-databases/fda-grantsaccelerated- approval-glofitamab-gxbm-selected-relapsed-or-refractory-large-bcell
  65. U.S. Food and Drug Administration. FDA DISCO Burst Edition: FDA approvals of Talvey (talquetamab-tgvs) for relapsed or refractory multiple myeloma. Retrieved December 1, 2025, from: https://www.fda.gov/drugs/ resources-information-approved-drugs/fda-disco-burst-edition-fda-approvalstalvey- talquetamab-tgvs-relapsed-or-refractory-multiple
  66. U.S. Food and Drug Administration. FDA DISCO Burst Edition: FDA approval of Epkinly (epcoritamab-bysp) for relapsed or refractory diffuse large B-cell lymphoma. Retrieved December 1, 2025, from: https://www.fda. gov/drugs/resources-information-approved-drugs/fda-disco-burst-edition-fdaapproval- epkinly-epcoritamab-bysp-relapsed-or-refractory-diffuse-large-b
  67. U.S. Food and Drug Administration. FDA grants traditional approval to tarlatamab-dlle for extensive-stage small cell lung cancer. Retrieved December 1, 2025, from: https://www.fda.gov/drugs/resources-information-approveddrugs/ fda-grants-traditional-approval-tarlatamab-dlle-extensive-stage-smallcell- lung-cancer
  68. Miao, Z., Levi, J., and Cheng, Z. (2011) Protein scaffold-based molecular probes for cancer molecular imaging. Amino Acids, 41(5), 1037–1047. DOI
  69. Simeon, R., and Chen, Z. (2018) In vitro-engineered non-antibody protein therapeutics. Protein & Cell, 9(1), 3–14. DOI
  70. Yu, X., Yang, Y.-P., Dikici, E., Deo, S.K., and Daunert, S. (2017) Beyond antibodies as binding partners: the role of antibody mimetics in bioanalysis. Annual Review of Analytical Chemistry, 10(1), 293–320. DOI
  71. Lee, Y.J., and Jeong, K.J. (2015) Challenges to production of antibodies in bacteria and yeast. Journal of Bioscience and Bioengineering, 120(5), 483–490. DOI
  72. Ochoa, M.C., Minute, L., Rodriguez, I., Garasa, S., Perez-Ruiz, E., Inogés, S., Melero, I., and Berraondo, P. (2017) Antibody-dependent cell cytotoxicity: immunotherapy strategies enhancing effector NK cells. Immunology and Cell Biology, 95(4), 347–355. DOI
  73. Wang, Y., Fan, Z., Shao, L., Kong, X., Hou, X., Tian, D., Sun, Y., Xiao, Y., and Yu, L. (2016) Nanobody-derived nanobiotechnology tool kits for diverse biomedical and biotechnology applications. International Journal of Nanomedicine, 11, 3287–3303. DOI
  74. Eyer, L., and Hruska, K. (2012) Single-domain antibody fragments derived from heavy-chain antibodies: a review. Veterinarni Medicina, 57(8), 439–513. DOI
  75. Luo, R., Liu, H., and Cheng, Z. (2022) Protein scaffolds: antibody alternatives for cancer diagnosis and therapy. RSC Chemical Biology, 3(7), 830–847. DOI
  76. Nilsson, B., Moks, T., Jansson, B., Abrahmsen, L., Elmblad, A., Holmgren, E., Henrichson, C., Jones, T.A., and Uhlen, M. (1987) A synthetic IgG-binding domain based on staphylococcal protein A. Protein Engineering, 1(2), 107–113. DOI
  77. Nord, K., Nilsson, J., Nilsson, B., Uhlén, M., and Nygren, P.A. (1995) A combinatorial library of an alpha-helical bacterial receptor domain. Protein Engineering, 8(6), 601–608. DOI
  78. Ståhl, S., Gräslund, T., Eriksson Karlström, A., Frejd, F.Y., Nygren, P.-Å., and Löfblom, J. (2017) Affibody molecules in biotechnological and medical applications. Trends in Biotechnology, 35(8), 691–712. DOI
  79. Dickinson, C.D., Veerapandian, B., Dai, X.P., Hamlin, R.C., Xuong, N.H., Ruoslahti, E., and Ely, K.R. (1994) Crystal structure of the tenth type III cell adhesion module of human fibronectin. Journal of Molecular Biology, 236(4), 1079-1092. DOI
  80. Frejd, F.Y., and Kim, K.T. (2017) Affibody molecules as engineered protein drugs. Experimental & Molecular Medicine, 49(3), e306. DOI
  81. Guo, X., Wang, Y., Yang, S., Bao, J., Liu, H., Huang, Y., Shi, G., Li, Z., Liu, D., Wang, M., Chen, M., and Zhang, X. (2024) Comparison of an Affibodybased molecular probe and 18F-FDG for detecting HER2-positive breast cancer at PET/CT. Radiology, 311(3), e232209. DOI
  82. Gabriele, F., Palerma, M., Ippoliti, R., Angelucci, F., Pitari, G., and Ardini, M. (2023) Recent advances on affibody- and DARPin-conjugated nanomaterials in cancer therapy. International Journal of Molecular Sciences, 24(10), 8680. DOI
  83. Petrovskaya, L.E., Shingarova, L.N., Dolgikh, D.A., and Kirpichnikov, M.P. (2011) Alternative scaffold proteins. Russian Journal of Bioorganic Chemistry, 37(6), 517–526. DOI
  84. Sha, F., Salzman, G., Gupta, A., and Koide, S. (2017) Monobodies and other synthetic binding proteins for expanding protein science. Protein Science, 26(5), 910–924. DOI
  85. Hinner, M.J., Giese, A., Buchholz, C.J., Frentsch, M., Hornig, N., Corzillus, V., ... and Ziegelbauer, K. (2019) Tumor-localized costimulatory T-cell engagement by the 4-1BB/HER2 bispecific antibody-Anticalin fusion PRS- 343. Clinical Cancer Research, 25(19), 5878–5889. DOI
  86. U.S. National Library of Medicine. ClinicalTrials.gov. Study of [PRS-343 in HER2-Positive Solid Tumors], Retrieved December 1, 2025, from: https://clinicaltrials.gov/study/NCT03330561
  87. Mosavi, L.K., Minor, D.L. Jr, and Peng, Z.-Y. (2002) Consensus-derived structural determinants of the ankyrin repeat motif. Proceedings of the National Academy of Sciences of the United States of America, 99(25), 16029–16034. DOI
  88. Binz, H.K., Stumpp, M.T., Forrer, P., Amstutz, P., and Plückthun, A. (2003) Designing repeat proteins: well-expressed, soluble and stable proteins from combinatorial libraries of consensus ankyrin repeat proteins. Journal of Molecular Biology, 332(2), 489–503. DOI
  89. Goldstein, J.R., Sosabowski, J., Livanos, M., Leyton, J., Vigor, K., Bhavsar, G., Nagy-Davidescu, G., Rashid, M., Miranda, E., Yeung, J., Tolner, B., Plückthun, A., Mather, S., Meyer, T., and Chester, K. (2014) Development of the designed ankyrin repeat protein (DARPin) G3 for HER2 molecular imaging. European Journal of Nuclear Medicine and Molecular Imaging, 42(2), 288–301. DOI
  90. Boersma, Y.L. (2018) Advances in the application of designed ankyrin repeat proteins (DARPins) as research tools and protein therapeutics. Methods in Molecular Biology, 1798, 307–327. DOI
  91. Vorobyeva, A., Bragina, O., Altai, M., et al. (2018) Comparative evaluation of radioiodine and technetium-labeled DARPin 9_29 for radionuclide molecular imaging of HER2 expression in malignant tumors. Contrast Media & Molecular Imaging, 2018, 6930425. DOI
  92. Proshkina, G., Deyev, S., Ryabova, A., Tavanti, F., Menziani, M.C., and Bezuglov, V.V. (2019) DARPin_9-29-targeted mini gold nanorods specifically eliminate HER2-overexpressing cancer cells. ACS Applied Materials & Interfaces, 11(38), 34645–34651. DOI
  93. Milczek, E.M. (2017) Commercial applications for enzyme-mediated protein conjugation: new developments in enzymatic processes to deliver functionalized proteins on the commercial scale. Chemical Reviews, 118(1), 119–141. DOI
  94. Avacta Group plc. Pipeline. Retrieved December 1, 2025, from: https:// avacta.com/pipeline/
  95. Sheng, W., Geng, J., Li, L., Shang, Y., Jiang, M., and Zhen, Y. (2020) An albuminbinding domain and targeting peptidebased recombinant protein and its enediyneintegrated analogue exhibit directional delivery and potent inhibitory activity on pancreatic cancer with Kras mutation. Oncology Reports, 43, 851- 863. DOI
  96. Gapizov, S.S., Petrovskaya, L.E., Shingarova, L.N., Kryukova, E.A., Boldyreva, E.F., Lukashev, E.P., Yakimov, S.A., Svirshchevskaya, E.V., Dolgikh, D.A., and Kirpichnikov, M.P. (2019) Fusion with an albumin-binding domain improves pharmacokinetics of an αvβ3-integrin binding fibronectin scaffold protein. Biotechnology and Applied Biochemistry, 66, 617-625. DOI
  97. Pollack, C.V., Reilly, P.A., van Ryn, J., Eikelboom, J.W., Glund, S., Bernstein, R.A., Dubiel, R., Huisman, M.V., Hylek, E.M., Kam, C.W., Kamphuisen, P.W., Kreuzer, J., Levy, J.H., Royle, G., Sellke, F.W., Stangier, J., Steiner, T., Verhamme, P., Wang, B., Young, L., and Weitz, J.I. (2017) Idarucizumab for dabigatran reversal - full cohort analysis. New England Journal of Medicine, 377(5), 431–441. DOI
  98. Liu, Y., Vorobyeva, A., Xu, T., Orlova, A., Hajizadeh, S., and Altai, M. (2021) Comparative preclinical evaluation of HER2-targeting ABD-fused Affibody® molecules 177Lu-ABY-271 and 177Lu-ABY-027: impact of DOTA position on ABD domain. Pharmaceutics, 13(6), 839. DOI
  99. Jussing, E., Lu, L., Grafström, J., Velikyan, I., Vorobyeva, A., Orlova, A., Andersson, K.G., Tolmachev, V., and Micke, P. (2020) [68Ga]ABY-028: an albumin-binding domain (ABD) protein-based imaging tracer for positron emission tomography (PET) studies of altered vascular permeability and predictions of albumin-drug conjugate transport. EJNMMI Research, 10(1), 106. DOI
  100. Klint, S., Feldwisch, J., Gudmundsdotter, L., Dillner Bergstedt, K., Gunneriusson, E., Höidén Guthenberg, I., Wennborg, A., Nyborg, A.C., Kamboj, A.P., Peloso, P.M., Bejker, D., and Frejd, F.Y. (2023) Izokibep: preclinical development and first-in-human study of a novel IL-17A neutralizing Affibody molecule in patients with plaque psoriasis. MAbs, 15(1), 2209920. DOI
  101. Wang, R., Hu, B., Pan, Z., Mo, C., Zhao, X., Liu, G., Hou, P., Cui, Q., Xu, Z., Wang, W., et al. (2025) Antibody-drug conjugates (ADCs): current and future biopharmaceuticals. Journal of Hematology & Oncology, 18, 51. DOI
  102. Haque, M., Forte, N., and Baker, J.R. (2021) Site-selective lysine conjugation methods and applications towards antibody-drug conjugates. Chemical Communications, 57(82), 10689–10702. DOI
  103. Wang, L., Amphlett, G., Blättler, W.A., Lambert, J.M., and Zhang, W. (2005) Structural characterization of the maytansinoid-monoclonal antibody immunoconjugate, huN901-DM1, by mass spectrometry. Protein Science, 14(9), 2436–2446. DOI
  104. Matos, M.J., Oliveira, B.L., Martinez-Sáez, N., Guerreiro, A., Cal, P.M.S.D., Bertoldo, J., Maneiro, M., Perkins, E., Howard, J., Deery, M.J., et al. (2018) Chemo- and regioselective lysine modification on native proteins. Journal of the American Chemical Society, 140(11), 4004–4017. DOI
  105. Alradwan, I.A., Alnefaie, M.K., AL Fayez, N., Alqarni, A.M., Alhakamy, N.A., and Alshehri, S. (2025) Strategic and chemical advances in antibody–drug conjugates. Pharmaceutics, 17(9), 1164. DOI
  106. Jackson, C.P., Fang, S., Benjamin, S.R., Alayi, T., Hathout, Y., Gillen, S.M., Handel, J.P., Brems, B.M., Howe, J.M., and Tumey, L.N. (2022) Evaluation of an ester-linked immunosuppressive payload: a case study in understanding the stability and cleavability of ester-containing ADC linkers. Bioorganic & Medicinal Chemistry Letters, 75, 128953. DOI
  107. Dosio, F., Stella, B., Milla, P., Della Pepa, C., Gastaldi, D., and Arpicco, S. (2014) Targeted cancer therapy: the roles played by antibody-drug and antibody-toxin conjugates. In Atta-ur-Rahman (Ed.) Topics in Anti-Cancer Research (Vol. 4, pp. 105–152). Bentham Science Publishers. DOI
  108. Lyon, R.P., Setter, J.R., Bovee, T.D., Doronina, S.O., Hunter, J.H., Anderson, M.E., Balasubramanian, C.L., Duniho, S.M., Leiske, C.I., Li, F., and Senter, P.D. (2014) Self-hydrolyzing maleimides improve the stability and pharmacological properties of antibody-drug conjugates. Nature Biotechnology, 32(10), 1059–1062. DOI
  109. Beck, A., Goetsch, L., Dumontet, C., and Corvaïa, N. (2017) Strategies and challenges for the next generation of antibody–drug conjugates. Nature Reviews Drug Discovery, 16(5), 315–337. DOI
  110. Fu, Z., Li, S., Han, S., Shi, C., and Zhang, Y. (2022) Antibody drug conjugate: the «biological missile» for targeted cancer therapy. Signal Transduction and Targeted Therapy, 7(1), 93. DOI
  111. Adhikari, P., Zacharias, N., Ohri, R., and Sadowsky, J. (2020) Site-specific conjugation to Cys-engineered THIOMAB™ antibodies. In L. N. Tumey (Ed.) Antibody-Drug Conjugates: Methods and Protocols (pp. 51–69). Springer. DOI
  112. Peng, H. (2021) Perspectives on the development of antibody-drug conjugates targeting ROR1 for hematological and solid cancers. Antibody Therapeutics, 4(4), 222–227. DOI
  113. Li, Q., Cheng, Y., Tong, Z., Liu, Y., Wang, Y., Wang, Y., Liu, J., Qian, X., Zhang, Z., Wang, H., et al. (2024) HER2-targeting antibody drug conjugate FS- 1502 in HER2-expressing metastatic breast cancer: a phase 1a/1b trial. Nature Communications, 15, 5158. DOI
  114. Hussain, A.F., Grimm, A., Sheng, W., Zhang, C., Al-Rawe, M., Bräutigam, K., Abu Mraheil, M., and Moepps, B. (2021) Toward homogenous antibody drug conjugates using enzyme-based conjugation approaches. Pharmaceuticals, 14(4), 343. DOI
  115. Dennler, P., Chiotellis, A., Fischer, E., Brégeon, D., Belmant, C., Gauthier, L., Lhospice, F., Romagne, F., and Schibli, R. (2014) Transglutaminase-based chemo-enzymatic conjugation approach yields homogeneous antibody–drug conjugates. Bioconjugate Chemistry, 25(3), 569–578. DOI
  116. Dudchak, R., Podolak, M., Holota, S., Nowak, J., and Bielawski, K. (2024) Click chemistry in the synthesis of antibody-drug conjugates. Bioorganic Chemistry, 143, 106982. DOI
  117. McKay, C.S., and Finn, M.G. (2014) Click chemistry in complex mixtures: bioorthogonal bioconjugation. Chemistry & Biology, 21(9), 1075–1101. DOI
  118. Scinto, S.L., Bilodeau, D.A., Hincapie, R., Lee, W., Nguyen, S.S., Xu, M., am Ende, C.W., Finn, M.G., Lang, K., Lin, Q., et al. (2021) Bioorthogonal chemistry. Nature Reviews Methods Primers, 1, 30. DOI
  119. Tornøe, C.W., Christensen, C., and Meldal, M. (2002) Peptidotriazoles on solid phase: [1,2,3]-triazoles by regiospecific copper(I)-catalyzed 1,3-dipolar cycloadditions of terminal alkynes to azides. The Journal of Organic Chemistry, 67(9), 3057–3064. DOI
  120. Wang, Q., Chan, T.R., Hilgraf, R., Fokin, V.V., Sharpless, K.B., and Finn, M.G. (2003) Bioconjugation by copper(I)-catalyzed azide-alkyne [3 + 2] cycloaddition. Journal of the American Chemical Society, 125(11), 3192–3193. DOI
  121. Sakamoto, K.M., Kim, K.B., Kumagai, A., Mercurio, F., Crews, C.M., and Deshaies, R.J. (2001) Protacs: chimeric molecules that target proteins to the Skp1-Cullin-F box complex for ubiquitination and degradation. Proceedings of the National Academy of Sciences of the United States of America, 98(15), 8554–8559. DOI
  122. Navon, A., and Ciechanover, A. (2009) The 26 S proteasome: from basic mechanisms to drug targeting. Journal of Biological Chemistry, 284(49), 33713–33718. DOI
  123. Sun, Y., Zhao, X., Ding, N., Gao, H., Wu, Y., Yang, Y., Zhao, M., Hwang, J., Song, Y., Liu, W., and Rao, Y. (2018) PROTAC-induced BTK degradation as a novel therapy for mutated BTK C481S induced ibrutinib-resistant B-cell malignancies. Cell Research, 28(7), 779–781. DOI
  124. Burslem, G.M., Smith, B.E., Lai, A.C., Jaime-Figueroa, S., McQuaid, D.C., Bondeson, D.P., Toure, M., Dong, H., Qian, Y., Wang, J., et al. (2018) The advantages of targeted protein degradation over inhibition: an RTK case study. Cell Chemical Biology, 25(1), 67-77.e3. DOI
  125. Coleman, K.G., and Crews, C.M. (2018) Proteolysis-targeting chimeras: harnessing the ubiquitin-proteasome system to induce degradation of specific target proteins. Annual Review of Cancer Biology, 2, 41–58. DOI
  126. Riching, K.M., Mahan, S., Corona, C.R., McDougall, M., Vasta, J.D., Robers, M.B., Urh, M., and Daniels, D.L. (2018) Quantitative live-cell kinetic degradation and mechanistic profiling of PROTAC mode of action. ACS Chemical Biology, 13(9), 2758–2770. DOI
  127. Hines, J., Gough, J.D., Corson, T.W., and Crews, C.M. (2013) Posttranslational protein knockdown coupled to receptor tyrosine kinase activation with phosphoPROTACs. Proceedings of the National Academy of Sciences of the United States of America, 110(22), 8942–8947. DOI
  128. Long, R., Zuo, H., Tang, G., Zhang, C., Yue, X., Yang, J., Luo, X., Deng, Y., Qiu, J., Li, J., and Zuo, J. (2025) Antibody-drug conjugates in cancer therapy: applications and future advances. Frontiers Immunol, 16:1516419. DOI
  129. Clague, M.J., Urbé, S., and Komander, D. (2019) The demographics of the ubiquitin system. Trends in Cell Biology, 29(5), 417–426. DOI
  130. Henning, R.K., Varghese, J.O., Das, S., Nag, A., Tang, G., Tang, K., Sutherland, A.M., and Heath, J.R. (2016) Degradation of Akt using proteincatalyzed capture agents. Journal of Peptide Science, 22(4), 196–200. DOI
  131. Mullard, A. (2021) Targeted protein degraders crowd into the clinic. Nature Reviews Drug Discovery, 20(4), 247–250. DOI
  132. Bondeson, D.P., Mares, A., Smith, I.E., Ko, E., Campos, S., Miah, A.H., Mulholland, K.E., Routly, N., Buckley, D.L., Gustafson, J.L., et al. (2015) Catalytic in vivo protein knockdown by small-molecule PROTACs. Nature Chemical Biology, 11(8), 611–617. DOI
  133. Winter, G.E., Buckley, D.L., Paulk, J., Roberts, J.M., Souza, A., Dhe- Paganon, S., and Bradner, J.E. (2015) Phthalimide conjugation as a strategy for in vivo target protein degradation. Science, 348(6241), 1376–1381. DOI
  134. Long, R., Zuo, H., Tang, G., Zhang, C., Yue, X., Yang, J., Luo, X., Deng, Y., Qiu, J., Li, J., and Zuo, J. (2025) Antibody-drug conjugates in cancer therapy: applications and future advances. Frontiers in Immunology, 16, 1516419. DOI
  135. Gangopadhyay, S., and Gore, K.R. (2022) Advances in siRNA therapeutics and synergistic effect on siRNA activity using emerging dual ribose modifications. RNA Biology, 19(1), 452–467. DOI
  136. Tang, G. (2005) siRNA and miRNA: an insight into RISCs. Trends in Biochemical Sciences, 30(2), 106–114. DOI
  137. Benizri, S., Gissot, A., Martin, A., Vialet, B., Grinstaff, M.W., and Barthélémy, P. (2019) Bioconjugated oligonucleotides: recent developments and therapeutic applications. Bioconjugate Chemistry, 30(2), 366–383. DOI