|Year : 2022 | Volume
| Issue : 1 | Page : 40-49
Radiobioconjugate targeted therapy in cancer, using radiolabeled mediated biological analogs: Desired qualities and selective targeting approach
Department of Chemistry, GLA University, Mathura, Uttar Pradesh, India
|Date of Submission||23-Oct-2021|
|Date of Acceptance||16-Dec-2021|
|Date of Web Publication||11-Mar-2022|
Department of Chemistry, GLA University, Mathura - 291 406, Uttar Pradesh
Source of Support: None, Conflict of Interest: None
Radiobioconjugate therapy, recommended as one of the effective modalities for the treatment of cancer cells, is based on the concept of delivering the localized radiation at the cellular level to the disease site using a biological moiety. The high tumor/nontumor ratio is the essentially a sine qua non for the successful execution of targeted therapy which is highly desired. The central problem associated to radiobioconjugate therapy is the small fraction of a radiobioconjugate localized to the tumor, while the major fraction of it is delivered to the nontarget organs (reticuloendothelial system deposition). The current article focuses on the better perceptive of the factors of understanding, which includes the selection and expansion of sophisticated molecular carriers, assortment of a suitable radionuclide based on the class of emission, linear energy transmit, and the material radiophysical half-life. In addition, a concern to the biochemical interactions taking place at the molecular level, selection of a specific targeting strategy for designing effective treatment regimes, and importantly the challenges associated to it have also been discussed.
Keywords: Antibody targeted therapy, monoclonal antibody, pretargeting strategies, radiobioconjugate, reticuloendothelial system uptake
|How to cite this article:|
Garg P. Radiobioconjugate targeted therapy in cancer, using radiolabeled mediated biological analogs: Desired qualities and selective targeting approach. Biomed Biotechnol Res J 2022;6:40-9
|How to cite this URL:|
Garg P. Radiobioconjugate targeted therapy in cancer, using radiolabeled mediated biological analogs: Desired qualities and selective targeting approach. Biomed Biotechnol Res J [serial online] 2022 [cited 2022 May 22];6:40-9. Available from: https://www.bmbtrj.org/text.asp?2022/6/1/40/339380
| Introduction|| |
Despite significant advances in the therapy of different cancers types, the treatment remains unsatisfactory for most cancer-types due to the lack of a selective targeting approach [Table 1] and [Figure 1]. Radiobioconjugate targeted therapy, an emerging modality for cancer therapy, is advocated over surgery and external radiation therapy, as it is able to seek out and destroy micro-metastases which are unknown in their distribution. Radiobioconjugate therapy relates to the specific and selective targeting of cancer (tumor cells) by the delivery of localized radiation using a biological molecule. The biological vehicle can be an antibody, peptide, or antisense nucleotide.,,,,, Among the biomolecules, in particular, monoclonal antibodies (MoAbs) and peptides are today in the forefront of new targeting molecules, being investigated for therapy, not only in cancer but also in the treatment of life-threatening infections, toxins, and other related autoimmune diseases. Biologically, radiobioconjugate targeting entails a molecule which has a relative specificity for tumor cells – the so called projectile, attached to a radionuclide with suitable physical characteristics – the nuclear warhead. This arrangement results in selective homing on to tumor cells with relatively nonaccumulation in normal cells [Figure 2]. An antibody although having a high specificity for tumor tissues is considered to be a “slow-bullet” for targeting cancer cells, since it requires a long time to accumulate in the lesions. However, the use of antibody fragments such as F (ab) 2 or F (ab) 1 is preferred, which displays a faster blood clearance than whole antibodies and also due to their reduced size, results in lowered body background activity by virtue of rapid renal excretion. The high specificity of antibodies can be oppressed most excellently by holding the deliverance of the radiolabel (diagnostic/therapeutic agent) to an instance when the tumor/nontumor ratio is most favorable.,,,,,
|Figure 2: Radiobioconjugate therapy: Interaction of a radiolabeled antibody conjugates with tumor (cancer) cells. Radiobioconjugate targeted therapy using avidin-biotin approach, enhances target/nontarget ratio by multiplication of 4:1 ratio at each avidin-biotin interaction, creating a force multiplier targeting effect|
Click here to view
|Table 1: Overview of different types of cancers with symptoms, statistics, and current treatment option|
Click here to view
| Selective Targeting Moieties|| |
The antibody biomolecule
The importance of MoAbs in radio-immunotherapy is determined by their exquisite specificity for an antigen. The immune system has developed an exceptional ability to generate a highly explicit antibody molecule that approves the detection of almost any unidentified substance (antigen) present in the body. Antibody belongs to the class of immunoglobulins, which are the effector products of β-lymphocytes. The different classes of immunoglobulin molecules such as immunoglobulin G (IgG), IgM, IgA, IgD, IgE together with their molecular weights and biological half-lives have been summarized in [Table 2].
|Table 2: Different classes of immunoglobulin (antibody) molecules with their biological half-lives|
Click here to view
The immunoglobulin molecule is a Y-shaped divalent molecule, consisting of two pairs of polypeptide chain of different sizes (two heavy chains of 52,000 Dalton and two light chains of 23,000 Dalton) which are held together by disulfide bonds.,,,,, A typical immunoglobulin molecule IgG, shown as [Figure 3], has two antigen binding regions Fab and one Fc component. Fc component belongs to that part of molecule which performs class-related functions. Fc moiety is formed from the stem of Y-shaped molecule, and the remaining part of “Y” called as the (Fab) 2 moiety.,,, The two different moieties can be separated by digesting the IgG molecule with Pepsin. Each limb of the (Fab) 2, i.e., a Fab fragment can be obtained by digesting the F (ab) 2 or the whole IgG molecule with Papain.
|Figure 3: Structure of a typical antibody-biomolecule. A Y-shaped molecule with two identical “heavy” and “light” polypeptide chains, held together by disulfide bonds. The “Fab” component is concerned with antigen recognition, while “Fc” component performs class related functions of antibodies|
Click here to view
The molecular basis of diversity of antigen binding function, i.e., the antibody activity resides in the variable region of the Fab component, while the Fc moiety is crucial for the effector mechanisms, such as complement activation. As regard radioimmunotargeting (RIT), the Fc moiety has been considered responsible for nonspecific uptake by the reticuloendothelial system predominantly in liver. The F (ab), F (ab) 1, (Fab) 2 fragments of MoAb can be more useful than whole antibody for radioimmuno detection. The reduced size of these fragments results in lowered body background by virtue of rapid renal excretion. These molecules or so called antibody fragments also differ substantially from the whole antibody in terms of molecular weight and charge. The fragments such as F (ab) 2 and F (ab) 1 lack the largely negative charged carbohydrate molecule found on the Fc segment of the entire antibody. These fragments are thus less negatively charged in comparison to whole antibody and therefore have a much fairer probability of piercing the capillaries and interstitial fluid space between tumor cells.,
Radiolabeled monoclonal antibody detection system: Desired qualities
- Specific for tumor
- Located on the surface for RIS/RIT
- Readily available to antibody
- Stimulate high titer antibody in animal, not host
- Remains on the surface for sufficient time for imaging.
- Specific for tumor
- Little or no cross reaction with normal tissues
- Does not lose function when labeled or modified
- Reacts with antigen with high specific activity
- It should not be itself antigenic
- Does not lose label.
The antigen-antibody complex:
- Remains on cell surface or internalized, i.e., not shed.
- Correct emission for function
- Short (β) for autoradiography/therapy.
- Single medium energy (γ) for imaging.
- Optimal half-life, i.e., neither too short nor too long
- Easily attached to antibody
- Does not alter antibody function
- Stable on the antibody
- If dissociates from the antibody, it should be rapidly excreted and should not home to the bone.
Parameters effecting monoclonal antibody use in vivo
- Label/ability to label
- Stability of antigen-antibody complex
- Mode of excretion
- Dose clearance from circulation and soft tissues.
- Cellular, subcellular, shell location
- Specificity of expression
- Availability for MoAb binding
- Homology or degree of homology with other molecules.
- Material properties; physical half-life; emission type energy
- Elemental properties; conjugate-solidity
- Scintigraphic properties
- Dose specificity/activity
- Outcome on antibody-immunoreactivity
- Dose-clearance; renal excretion.
- Expression for antigen
- Number of antigen molecule on the cell surface
- Turnover, degradation or internalization
- Vascularity of tumor
- Size of tumor
- Depth of tumor from body surface
- Location of tumor
- Target/nontarget ratio
- Circulation of target antigen in other organs or body fluids
- Antigen modulation; antigen/epitope density.
- Dose of antibody, radioisotope
- Existence or nonexistence of anti-MoAb in the host
- Existence or nonexistence of circulating antigen and complex
- Choice of label
- Route of administration
- Time after administration before localization
- Subtraction techniques
- Imaging system PLANAR/SPECT (for RIS)
Peptides: An emerging targeting bio-molecule
Peptides are emerging as therapy molecules alternate to the MoAbs. They have been recommended to use for therapy and for the diagnosis in radiolabeled form. The receptor-assisted peptide moieties have emerged as an essential substitute to other traditional treatment options for primary and secondary metastatic tumors. Receptor fervent peptides have been considered as an ideal deliverance vehicles for selective allocation of radioemitters to malignant cancer cells, ensuing diseased cell fatality.,,,,,
Peptides versus antibodies, which is the better option as a targeting moiety?
As compared to antibodies (m. w. = 200,000), the molecular size of the peptide is much smaller, <10,000 kilo-Dalton and for small peptides <35.00 kilo-Dalton. Since they are smaller molecules, their clearance from the blood after injection is more rapid, allowing earlier imaging. The affinity of peptides for their receptors is greater than that of antibodies for antigens. Peptides can tolerate harsher labeling conditions than antibodies and are less likely to be immunogenic. Peptides can be easily synthesized and do not depend on a biological system for manufacture. However, peptides undergo rapid lysis in vivo and need molecular engineering to enhance their in vivo life, such as the substitution of peptides bonds, use of D-amino acids, replacement of disulfide bonds by thio-ether linkages, insertion of unusual D-amino acids, terminal capping, N-methylation, cyclization, and replacement of amino by imino groups.,,,
Peptides that have attracted interest for tumor diagnosis or therapy include octreotide/depreotide/vapreotide/vasoactive intestinal peptide/cholecystokinin analogs/bombesin analogs and calcitonin analogs. Octreotide and its analogs are already commercially successful not only in tumor but also for treatment of gastrointestinal bleeds and life-threatening pancreatitis. Somatostatin receptors are crucial membrane glycoproteins that are circulated in a range of tissues all over the body. Somatostatin analogs, promising for peptide receptor radionuclide therapy (PRRT) and peptide receptor radionuclide scintigraphy includes Tyr3-Octreotide and Tyr3-Octreotate. For therapeutic applications, the tetra-azacyclododecane tetra-acetic acid, derivatives of Tyr3-Octreotide and Tyr3-Octreotate reported to form a stable radiolabeled conjugate with Yttrium (Y-90) and Lutetium (Lu-177) radionuclides, respectively, and are used in treating somatostatin receptor-positive tumor models.,,
| Criteria for Selecting an Ideal Therapy Radionuclide|| |
The prime objective of targeted radiobioconjugate therapy is the deliverance of absorbed radiations specifically to the diseased site, with subsequent minimization of it to the normal tissues. In developing a preeminent radioimmuno therapeutic management, several factors of importance have to be consider during the course of treatment, which include the assortment of an antigen, the selection of a suitable antibody, and most importantly the choice of an appropriate radionuclide against it. The selection of a radionuclide will depend upon whether it is required for diagnostic purpose or for the therapeutic application. A tabular representation of different selective radionuclide on the basis of their suitability for imaging and therapy purposes has been shown in [Table 3]. Some common requirements for selecting a radionuclide for radioimmunotherapy are as follows:,,,,
|Table 3: Principal radionuclides used for antibody-targeted imaging and therapy: Low-to-intermediate β energy (suitable for γ emission for imaging >10% abundance)|
Click here to view
- Standardized chemical preparation
- Preferable linkage to immunoglobulin (antibody) through bi-functional chelate
- Isotopic half-life compatible with biological time course of accumulation in tumor (1–3 days)
- Availability with high specific activity and radiochemical purity
- Lack of biological toxicity in dose used.
The two principal determinants in selection of a radionuclide for radioimmuno targeting are photon energy and half-life., The ideal characteristic of a radionuclide used for the treatment purposes include its energy type and emissions required for the optimal local energy deposition within the tumor and minimal dose to background organs. If required for scintigraphic or imaging purposes, a radionuclide must be as such which emits low penetrating radiation, escaping the whole body radiation and can easily be detected by a scanning tool.,,,
The physical half-time of a radionuclide should be in consistent with the in vivo pharmacokinetics of the antibody, i.e., homing of the antibody to the tumor (which occurs over a period of 3–5 days) and its clearance from the background tissues. If the physical half-life is too small, majority of the radioactive decay would occur much before the MoAb has achieved maximum tumor/nontumor ratio and thus delivering a large fraction of its dose to the nonspecific organs. On the other side if the half-life (T1/2) is significantly high, it can cause superfluous emissions to the normal body cells, even after their clearance from the main tumor lump. Further, it would be desired that the half-life (T1/2) of the radionuclide should permit its wide-spread distribution from the production sites. Practically, two or more half-lives should provide an adequate time-period for the production and shipping of a radionuclide to a research unit.,,
Radiobiological effects and their concern for improved targeting efficacy
Radiobiological considerations also play a prominent role in selection of radionuclides. It has been demonstrated that the body residence time for a complete antibody of the type IgG is much longer than that of its fragments F (ab1) 2, Fab, or Fc. Thus, radioimmunotherapy with whole IgG molecule would be most effective when using long lived radionuclides with a physical half-life ranging 4–8 days. However, radionuclides with shorter half-lives 1–3 days would be more effective when utilizing the agents with rapid accumulation in tumors and faster clearance from nontumor organs. The suitability of a radionuclide for RIT depends on variety of other factor also, such as the nuclide radiophysical properties, the target tumor morphology and physiology, the antibody targeting kinetics, the in vivo stability of the radionuclide, the radionuclides accessibility, the availability of simple and efficient clinical scale radiolabeling methods, and importantly the nature of radiation, such as low or high linear energy transfer.,
The fact that radiobioconjugate targeting mainly concern for much improved deliverance of the radioactive dose to tumor cells, but sometimes the desired therapeutic success may not achieve due to poor understanding about the fate of the injected dose delivered, cellular heterogeneity developed in the tumor mass, radiobiological responses offered by the neighboring cells, potency of the dose absorbed, i.e., target versus nontumor ratio, plays a vital role in determining the clinical efficacy of any therapeutic modality. The radiosensitivity of the tumor is generally governed by certain radiobiological phenomenon such as genomic instability, by-stander effect, adaptive response, minimal dose requirement, and hyper radiosensitivity.
There are sufficient evidences, that the injected absorbed dose in a well-established radio-immunotherapy cancer treatment scheme is related to the biological response that it will produce inside the body. These biological effects in turn are directly correlated to the rate at which a given injected dose is delivered or absorbed on a tumor. This can be figure out as such, if a dose of 30 millicurie delivered to a tumor for over a period of several weeks, with a rate that is constantly declining, it will have a very divergent effect in comparison to an equivalent dose amount, delivered at much elevated dose rate. The difference in biological outcome will result in both cases and that depends on the biological repair and radiosensitivity assets of the tumor. These concepts have been well established and few studies based on using in vivo and in vitro models explore the possibilities for better understanding of radiobiological concerns, for much improved tumor cell targeting.
| Labeling Techniques for Radioimmuno Targeting|| |
Direct versus Indirect multistep pretargeting approach: Which is the better option?
Conventional MoAb targeting approach, involving a direct radiolabeling of antibodies, is identified with slow pharmacokinetics. The circulating half life of a MoAb in the blood is usually between 2 to 4 days. This long dwelling time of antibody in the blood although facilitates its most favorable accretion in the tumor, but it also causes a high retention period in the nontarget tissues. To enhance the therapeutic competence of radioimmuno therapy of cancer, i.e., (high selective tumor uptake and minimization of nontarget tissue background activity), multistep pretargeting approaches have been investigated and recommended by different scientist groups. These multistep pretargeting approaches have received substantial attention both for cancer scintigraphy and therapy, as these represents a highly selective substitution to ordinary targeting systems, based on direct radiolabeling of antibodies.,,
Divergent from the direct targeting systems, where an effector moiety, i.e., a radionuclide or a drug conjugated to a low-molecular-weight carrier is directly attached to a targeting agent, in pretargeting systems, the deliverance of an effector moiety is delayed for some time after the administration of the targeting agent (antibody). This endow sufficient time for the targeting agent to confined in the tumor tissues and more importantly to get excreted and cleared from the nontarget cells in the body and circulation. Later, the radionuclide is administered link to a small ligand molecule that acts as a rapid blood clearing agent, to maximize its accumulation in the tumor and minimizing exposure to the nontarget tissues. The radiolabeled ligand allocates rapidly all through the body and attach to the prelocalized antibodies in the malignant tissues, while the unbound radiolabeled molecules washed rapidly from the body.,, Biochemically, pretargeting involves a prior deliverance of a targeting moiety (MoAb) in the circulation, which is having a good empathy and a noncovalent binding site for an effector molecule (radionuclide), which is injected later once the MoAb has concentrated in the target tumor perfectly, [Figure 4].
|Figure 4: Three step pretargeting scheme: Streptavidin conjugated antibodies injected intravenously in tumor *(first step); after 2–4 days injection of galactosylated albumin-biotin *(second step); followed by 48 h later by injection of radiolabeled biotin|
Click here to view
Pretargeting strategies have been identified to enhance tumor delivery of therapy isotopes and this has led to programs to link biotin/avidin/chelates both for the diagnostic and therapeutic isotopes. Different reagents have been recommended for an antibody directed pretargeting approaches, most of them achieving improved tumor/nontumor radioactivity ratio. These include MoAb-Avidin/Biotin, MoAb-Biotin/Avidin, MoAb-Enzyme/Prodrug, MoAb/hapten, and MoAb-Oligonucleotide/antisense-Oligonucleotide, highlighted in [Table 4]. The ultimate endeavor of attempting all these approaches is to maximize the accumulation of radiolabeled MoAbs in the tumor tissues and to minimize their deliverance to nontumor tissues.,,,
|Table 4: Tabular representation of different pretargeting approaches based on avidin-biotin approach|
Click here to view
| Future Prospectives and Challenges|| |
There is good evidence that nuclear medicine can help in the identification and localization of initial tumors and secondary metastases, by the assessment of chosen therapy and the recognition of its recurrence. Advances in understanding immunological features of cancer cells have paved the way toward more precise uses of radiolabeled antibodies. The ability to produce MoAbs by the so called “Hybridoma technology” led to a quantam leap in tumor immunology. There has been considerable progress in targeting of diagnostic and therapeutic radioisotopes to the tumor using these MoAbs.,
RIT has now expanded from a limited experimental approach to an advanced clinical modality. Antibody-radionuclide targeted therapy research and its clinical implimentation are advancing rapidly. Development of new targeting moieties for cancer cells such as gastrin-releasing peptide receptors, chemokine receptors, folate receptor, and others has provided additional opportunities to move forward. The incorporation of high-energy alpha emitter radionuclides (213Bi, 211At, 225Ac) and beta emitters (171Lu, Au, 111Ag, 186/188Re) has provided imprecented opportunities for more selective therapeutic treatment of cancer cells. The two advanced radiolabeled antibodies for the treatment of Non-Hodgkin's Lymphoma (NHL), involve the conjugation of two intact anti-CD-20 antibodies ibritumomab tiuxetan coupled with yttrium-90 forming Zevalin and other CD-20 antibody tositumomab linked to Iodine-131 result in Bexxar. New developments in radionuclidic targeted therapy are emerging constantly and are in a phase of new innovations. The use of targeted radionuclidic therapy for imaging and targeting the disease site has been increasingly accepted. The imaging studies evaluated through positron emission tomography/computed tomography for detecting prostrate cancers and the use of radiotracers for targeting prostrate specific membrane antigen as a pretherapy markers, the use of novel treatment modalities like radiovirotherapy for deliverance of the radionuclides into malignant cancer cells, are some of the related current and futuristic development pertaining to antibody guided targeted radionuclidic therapy.,,,
The miraculous capability of the radiobioconjugate therapy against major cancers and secondary metastasis is recognized as an effective and safe treatment regimen. The 5-year survival success rate for different types of cancers involving radiobioconjugate therapy either unaided or in combination with other treatment modalities is shown in [Table 5] and [Figure 5]. The latest endorsement of β-particle emitting radiopharmaceutical reagents for neuroendocrine cancers and the authorization of α-emitter for bone metastasis of prostrate cancer has reignited the interest. PRRT is an emerging selective targeted therapy, use of peptides radiolabeled with Yttrium (Y-90) and Lutetium Lu-177 isotopes to deliver radiations selectively to those cancer cells that articulate somastatin receptors. There has been a significant interest in (PRRT) because of its advantages innate to the radionuclidic therapy at the molecular level and allows minimal toxicity to nontargeted tissues. From the last few years, a preclinical combinational study of radiotherapy with other immune stimulants such as vaccines or cytokines or combinational antibodies that can target immunosupressive molecules like immune checkpoint inhibitors. Some of the related advancements are currently tested and are under clinical trials. Although radiobioconjugate targeting has established itself as a helpful cancer treatment modality in comparison to other standard approaches, for more than 4 decades of a clinical investigation, RBT has not found its place in the same way as other therapies. One of the important reasons for that is not only the public prescription for the fright of radioactivity but also the intricacy of the treatment. The lack of an expertise medical staff to handle this new treatment modality and also a need of suitable skilled training programs for effective deliverance of radio-bioconjugate drugs.,
|Figure 5: Chart representing a comparative survival success rate for different types of cancers involving radiobioconjugate therapy versus other treatment modalities under various stages of cancer|
Click here to view
|Table 5: Comparative survival success rate for different cancer types with radiobioconjugate therapy versus other treatment modalities|
Click here to view
| Conclusion|| |
Radiobioconjugate therapy has an advantage in maximizing the selective targeting effect and limiting the dose toxicity. However, it can be challenging to implement this treatment modality in common, due to its expensive and complex nature. There is a grooming need for education and multidisciplinary awareness and also collaboration among scientists, industrial, and medical communities. Adoption of a practical approach to manufacture and timely delivery of radiopharmaceuticals, assessing patient eligibility and optimizing posttherapy effect with constant follow-up are some of the issues that are essential and need an urgent attention for its success.
I would like to acknowledge the support of my esteemed teacher and guide, Professor D. K. Hazra, eminent scientist and professor for his constant motivation and support. I would also like to thank my niece and nephew for collecting the statistical analysis data for the survival success rate for different types of cancer.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Mohan G, Hamna TP, Jijo AJ, Devi KM, Narayanasamy A, Vellingiri B. Recent advances in radiotherapy and its associated side effects in cancer a review. J Basic Appl Zool 2019;80:14.
Czerwinska M, Bilewicz A, Kruszewski M, Wegierek-Ciuk A, Lankoff A. Targeted radionuclide therapy of prostate cancer-from basic research to clinical perspectives. Molecules 2020;25:1743.
Kawashima H. Radioimmunotherapy: A specific treatment protocol for cancer by cytotoxic radioisotopes conjugated to antibodies. Sci World J 2014;2014:492061.
Gill MR, Falzone N, Du Y, Vallis KA. Targeted radionuclide therapy in combined-modality regimens. Lancet Oncol 2017;18:414-23.
Dolgin E. Radioactive drugs emerge from the shadows to storm the market. Nat Biotechnol 2018;36:1125-7.
Seebacher NA, Stacy AE, Porter GM, Merlot AM. Clinical development of targeted and immune based anti-cancer therapies. J Exp Clin Cancer Res 2019;38:156.
Pérez-Herrero E, Fernández-Medarde A. Advanced targeted therapies in cancer: Drug nanocarriers, the future of chemotherapy. Eur J Pharm Biopharm 2015;93:52-79.
Goldsmith SJ. Targeted radionuclide therapy: A historical and personal review. Semin Nucl Med 2020;50:87-97.
Kruger S, Ilmer M, Kobold S, Cadilha BL, Endres S, Ormanns S, et al
. Advances in cancer immunotherapy 2019 latest trends. J Exp Clin Cancer Res 2019;38:268.
Liu X, Yi Y. Recent updates on Sintilimab in solid tumor immunotherapy. Biomark Res 2020;8:69.
Zhang Y, Zhang Z. The history and advances in cancer immunotherapy: Understanding the characteristics of tumor-infiltrating immune cells and their therapeutic implications. Cell Mol Immunol 2020;17:807-21.
Xie YH, Chen YX, Fang JY. Comprehensive review of targeted therapy for colorectal cancer. Sig Transduct Target Ther 2020;5:22.
Lu RM, Hwang YC, Liu IJ, Lee CC, Tsai HZ, Li HJ, et al
. Development of therapeutic antibodies for the treatment of diseases. J Biomed Sci 2020;27:1.
Zahavi D, Weiner L. Monoclonal antibodies in cancer therapy. Antibodies 2020;9:34.
Dixon, KJ, Wu J, Walcheck B. Engineering anti-tumor monoclonal antibodies and Fc receptors to enhance ADCC by human NK cells. Cancers 2021;13:312.
Huang S, Van-Duijnhoven SM, Sijts AJ Elsas AV. Bispecific antibodies targeting dual tumor-associated antigens in cancer therapy. J Cancer Res Clin Oncol 2020;146:3111-22.
Kaplon H, Muralidharan M, Schneider Z, Reichert JM. Antibodies to watch in 2020. mAbs 2020;12:1.
Larson SM, Carrasquillo JA, Cheung NK, Press OW. Radioimmunotherapy of human tumors. Nat Rev Cancer 2015;15:347-60.
Candelaria PV, Sum LL, Penichet ML, Daniels-Wells TR. Antibodies targeting the transferrin receptor 1 (TfR1) as direct anti-cancer agents. Front Immunol 2021;12:583.
Zhong L, Li Y, Xiong L, Wang W, Wu Mi, Yuan T, et al
. Small molecules in targeted cancer therapy: Advances, challenges, and future perspectives. Sig Transduct Target Ther 2021;6:201.
Umotoy JC, DeTaeye SW. Antibody conjugates for targeted therapy against HIV-1 as an emerging tool for HIV-1 cure. Front Immunol 2021;12:708806.
Rosenblum D, Joshi N, Tao W, Karp JM, Peer D. Progress and challenges towards targeted delivery of cancer therapeutics. Nat Commun 2018;9:1410.
Khongorzul P, Ling CJ, Khan FU, Ihsan, AU, Zhang J. Antibody-drug conjugates: A comprehensive review. Mol Cancer Res 2020;18:3-19.
Wang S, Chen K, Lei Q, Ma P, Yuan AQ, Zhao Y, et al
. The state of the art of bispecific antibodies for treating human malignancies. EMBO Mol Med 2021;13:e14291.
Hoppenz P, Els-Heindl S, Beck-Sickinger AG. Peptide-drug conjugates and their targets in advanced cancer therapies. Front Chem 2020;8:571.
Thundimadathil J. Cancer treatment using peptides: Current therapies and future prospects. J Amino Acids 2012;2012:967347.
Cooper BM, O'Donovan DH, Halvarsson MO, Spring, DR. Peptides as a platform for targeted therapeutics for cancer: Peptide drug conjugates PDCs. Chem Soc Rev 2021;50:1480-94.
Alas M, Saghaeidehkordi A, Kaur K. Peptide-drug conjugates with different linkers for cancer therapy. J Med Chem 2021;64:216-32.
Mehrotra N, Kharbanda, S, Singh H. Peptide-based combination nanoformulations for cancer therapy. Nanomedicine 2020;15:2201-17.
Ayo A, Laakkonen P. Peptide-based strategies for targeted tumor treatment and imaging. Pharmaceutics 2021;13:481.
Park JY, Shin Y, Won WR, Lim C, Kim JC, Kang K, et al
. Development of AE147 peptide-conjugated nanocarriers for targeting uPAR-overexpressing cancer cells. Int J Nanomed 2021;16:5437-49.
Cheng Z, Li M, Dey R, Chen Y. Nanomaterials for cancer therapy: Current progress and perspectives. J Hematol Oncol 2021;14:85.
Eychenne R, Bouvry C, Bourgeois M, Loyer P, Benoist E, Lepareur N, et al
. Overview of radiolabeled somatostatin analogs for cancer imaging and therapy. Molecules 2020;25:4012.
Worm DJ, Heindl SE, Beck-Sickinger AG. Targeting of peptide-binding receptors on cancer cells with peptide-drug conjugates. Peptide Sci 2020;112:e24171.
Kolasińska-Cwikła A, Lowczak A, Maciejkiewicz KM, Ćwikła JB. Peptide receptor radionuclide therapy for advanced gastroenteropancreatic neuroendocrine tumors from oncology perspective. Nucl Med Rev Cent East Eur 2018;21(2):19. doi:10.5603/NMR.2108.0019.
Feijtel D, de Jong M, Nonnekens J. Peptide receptor radionuclide therapy: Looking back, looking forward. Curr Top Med Chem 2020;20:2959-69.
Bodei L, Ćwikla JB, Mark KM, Modlin IM. The role of peptide receptor radionuclide therapy in advanced/metastatic thoracic neuroendocrine tumor. J Thorac Dis 2017;9 Suppl 15:s1511-21.
White JM, Escorcia FE, Viola NT. Perspectives on metals-based radioimmunotherapy (RIT): Moving forward. Theranostics 2021;11:6293-314.
Jadvar H. Targeted radionuclide therapy: An evolution toward precision cancer treatment. Am J Roentgenol 2017;209:277-88.
Puttemans J, Dekempeneer Y, Eersels JL, Hanssens H, Debie P, Keyaerts M, et al
. Preclinical targeted α-and β-radionuclide therapy in HER2-positive brain metastasis using camelid single-domain antibodies. Cancers 2020;12:1017.
Srivastava SC. Criteria for the selection of radionuclides for targeting nuclear antigens for cancer radioimmunotherapy. Cancer Biother Radiopharm 2009;11;43-50.
Payolla FB, Massabni AC, Orvig C. Radiopharmaceuticals for diagnosis in nuclear medicine: A short review. Eclet Quim J 2019;44:11-9.
Zimmerman RG. Industrial constraints in the selection of radionuclides and the development of new radiopharmaceuticals. World J Nucl Med 2008;7:126-34.
Hazra DK, Garg P. Pretargeting in radiobioconjugate therapy: With reference to rhenium, gold and lutetium as candidate therapy isotopes. Indian J Nucl Med 2007;22:1-8. [Full text]
Mikolajczak R, Huclier-Markai S, Alliot C, Haddad F, Szikra D, Forgacs V, et al
. Production of scandium radionuclides for theranostic applications: Towards standardization of quality requirements. EJNMMI Radiopharm Chem 2021;6:19.
Aime S, Al-Qahtani M, Behe M, Bormans G, Carlucci G, Da-silva JN, et al
. Highlight selection of radiochemistry and radiopharmacy developments by editorial board. EJNMMI Radiopharm Chem 2021;6:13.
Witney TH, Blower PJ. The chemical tool-kit for molecular imaging with radionuclides in the age of targeted and immune therapy. Cancer Imaging 2021;21:18.
Michiel VD, Charlotte D, Reinhard H, Laura L, Eric C, Thomas S, et al
. Production of Sm-153 with very high specific activity for targeted radionuclide therapy. Front Med (Lausanne) 2021;8:675221.
Wolf W, Shahni J. Criteria for the selection of the most desirable radionuclide for radiolabeling monoclonal antibodies. Int J Rad Appl Instrum B 1986;13:319-24.
Jadiyappa S. Radioisotope: Applications, Effects, and Occupational Protection. London: IntechOpen; 2018.
James SS, Bednarz B, Benedict S, Buchsbaum, JC, Dewaraja Y, Frey E, et al
. Current status of radiopharmaceutical therapy. Int J Radiat Oncol Biol Phys 2021;109:891-901.
Kumar C, Shetake N, Desai S, Kumar A, Samuel G, Pandey BN, et al
. Relevance of radiobiological concepts in radionuclide therapy of cancer. Int J Rad Biol 2016;92:1-14.
Pouget JP, Lozza C, Deshayes C, Boudousa V, Teullon IN. Introduction to radiobiology of targeted radionuclide therapy. Front Med 2015;2:12.
Pouget JP, Coustanzo J. Revisiting the radiobiology of targeted alpha-therapy. Front Med 2021;8:692436.
Aerts A, Eberlein U, Holm S, Hustinx R, Koninjenberg M, Strigari L, et al
. EANM position paper on the role of radiobiology in nuclear medicine. Eur J Nucl Med Mol Imaging 2021;48:3365-77.
Peltek OO, Muslimov AR, Zyuzin MV. Current outlook on radionuclide delivery systems: From design consideration to translation into clinics. J Nanobiotechnol 2019;17:90.
Hapuarachchige S, Artemov D. Theranostic pretargeting drug delivery and imaging platforms in cancer precision medicine. Front Oncol 2020;10:1131.
Parker CL, McSweeney MD, Lucas AT, Jacobs TM, Wadsworth D, Zamboni WC, et al
. Pretargeted delivery of PEG-coated drug carriers to breast tumors using multivalent, bispecific antibody against polyethylene glycol and HER2. Nanomedicine 2019;21:102076.
Yadav P, Jain J, Sherje AP. Recent advances in nanocarriers-based drug delivery for cancer therapeutics: A review. React Funct Polym 2021;165:104970.
Steen EJ, Edem PE, Nørregaard K, Jørgensen JT, Shalgunov V, Kjaer A, et al
. Pretargeting in nuclear imaging and radionuclide therapy: Improving efficacy of theranostics and nanomedicines. Biomaterials 2018;179:209-45.
Myrhammar A, Vorobyeva A, Westerlund K, Yoneoka S, Orlova A, Tsukahara T, et al
. Evaluation of an antibody-PNA conjugate as a clearing agent for antibody-based PNA-mediated radionuclide pretargeting. Sci Rep 2020;10:20777.
Nazarova L, Rafidi H, Mandikian D, Ferl GZ, James T, Koerber JT, et al
. Effect of modulating FcRn binding on direct and pretargeted tumor uptake of full-length antibodies. Mol Cancer Ther 2020;19:1015.
Au KM, Wang AZ, Park SI. Pretargeted delivery of PI3K/mTOR small-molecule inhibitor-loaded nanoparticles for treatment of non-Hodgkin's lymphoma. Sci Adv 2020;6:eaaz9798.
Gulec BA, Yurt F. Treatment with radiopharmaceuticals and radionuclides in breast cancer: Current options. Eur J Breast Health 2021;17:214-9.
Watering FC, Rijpkema M, Robillard, M, Oyen WJG, Boermann OC. Pretargeted imaging and radioimmunotherapy of cancer using antibodies and bioorthogonal chemistry. Front Med 2014;1:44.
Sgouros G, Bodei L, McDevitt MR, Nedrow JR. Radiopharmaceutical therapy in cancer: Clinical advances and challenges. Nat Rev Drug Discov 2020;19:589-608.
Zukotynski K, Jadvar H, Capala J, Fahey F. Targeted radionuclide therapy: Practical applications and future prospects. Biomark Cancer 2016;18:35-8.
Fleischmann M, Glatzer M, Rodel C, Tselis N. Radioimmunotherapy: Future prospects from the perspective of brachytherapy. J Contemp Brachyther 2021;13:458-67.
Hafeez MN, Celia C, Petrikaite V. Challenges towards targeted drug delivery in cancer nanomedicines. Processes 2021;9:1527.
Hiltunen JV. Search for new and improved radiolabeling methods for monoclonal antibodies: A review of different methods. Acta Oncol 1993;32:831-9.
Garg P, Hazra DK. Conjugation of antibodies with radiogold nanoparticles as an effector targeting agents in radiobioconjugate cancer therapy: Optimized labeling and biodistribution results. Indian J Nucl Med 2017;32:296-303.
] [Full text]
Gaipl US, Multhoff G, Pockley AG, Rodel F. Radioimmunotherapy-translational opportunities and challenges. Front Oncol 2020;10:190.
Bodere FK, Barbet J, Chatal JF. Radioimmunotherapy from current clinical success to future industrial breakthrough. J Nucl Med 2016;57:329-33.
[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]