The Role of Radiolabeled Monoclonal Antibodies in Cancer Imaging and ADC Treatment

Abstract

Antibody-drug conjugates (ADCs) are designed to deliver cytotoxic payloads to distinctive target-expressing cancer cells. Following internalization, the ADCs are routed to different compartments in the cells, where cleavage of the linker causes release of the cytotoxic cargo. With such a delivery system, more effective payloads can reach cancer cells, allowing for more efficient treatment and dosing schedule. The monoclonal antibody (mAb) component of ADC plays a crucial role in the effective targeting of cancer cell-specific antigens while minimizing binding to normal cells. Often, the same mAbs used in ADCs can be labeled instead with radionuclides suitable for positron emission tomography or gamma-camera scintigraphy. To achieve high sensitivity and specificity for imaging, radiolabeled mAbs must have high affinity for the antigen, favorable pharmacokinetic properties, and a low toxicity profile. The use of radiolabeled mAbs permits the noninvasive interrogation of specific target expression on tumor cells and assessment of tumor heterogeneity in vivo by a simple diagnostic imaging scan that may include the whole body in the field of view. With this approach, radiolabeled mAbs can serve as important imaging biomarkers to predict the optimal delivery of ADCs to tumors and be used to monitor therapy with follow-up scans. Moreover, the same mAb can then be radiolabeled with an analogous radionuclide for the delivery of β-emitters, α-particles, or Auger electrons as part of a radioimmunotherapy approach. The purpose of this review is to introduce key concepts regarding radiolabeled mAbs targeting various tumor antigens (CD20, CDH3, type I insulinlike growth factor receptor, prostate-specific membrane antigen, and human epidermal growth factor receptor 2) that are being used in the clinical setting or undergoing development.

Drug conjugates for the treatment of lung cancer: from drug discovery to clinical practice

“…RDCs replace cytotoxic drugs with nucleotides, which can be conjugated with antibodies to form radionuclide-antibody conjugates (RACs) [318]. RDCs are emerging precision tumor therapy drugs that utilize tumor antigen-specific molecular carriers for delivery, accurately targeting radionuclides to tumors for brachytherapy [319]. The mechanisms of the therapeutic effect of RDCs on tumors are as follows: (1) After the radiolabeled antibody specifically targets the membrane antigen on the tumor surface, the radionuclide directly damages DNA, mitochondrial DNA, the cell membrane, etc.…”

Antibody-Drug Conjugates in Lung Cancer: Recent Advances and Implementing Strategies

“…Some examples of noncytotoxic payloads in ADCs include1. Radioisotopes, therefore with ADCs delivering radiation directly to cancer cells 85 ;2. Enzymes: ADCs carrying enzymes can be used to target and degrade specific proteins in the cancer cells, leading to cell death 86 ;3.…”

The inverse electron demand Diels–Alder cycloaddition with carbon‐11 and fluorine‐18: A gateway to pretargeted imaging across the blood–brain barrier

“…Finally, the pharmacokinetic properties of the antibody or antibody fragment in relation to the imaging timepoints are also a key consideration when designing imaging experiments using such species. The PET imaging (and treatment) of a variety of cancers and other disorders in the periphery using highly selective and specific monoclonal antibodies and antibody fragments has revolutionised our understanding of these conditions over the last 10 years 2,25–30 . Studies in this area have highlighted the fact that these large molecules tend to be slow to accumulate at their target site and are also slow to clear from the circulation.…”

“…The PET imaging (and treatment) of a variety of cancers and other disorders in the periphery using highly selective and specific monoclonal antibodies and antibody fragments has revolutionised our understanding of these conditions over the last 10 years. 2,[25][26][27][28][29][30] Studies in this area have highlighted the fact that these large molecules tend to be slow to accumulate at their target site and are also slow to clear F I G U R E 3 Nomenclature and reactivity of TCOs: s-TCO and d-TCO adopt half-chair conformation making them more reactive, whereas higher reactivity of oxoTCO, which adopts crown conformation, is likely due to electron density of oxygen in the ring. from the circulation.…”