Economics of Antibody Drug Conjugates (ADCs): Innovation, Investment and Market Dynamics.

PURPOSE OF REVIEW: This review aims to explore the intricate interplay between scientific advancements and economic considerations in the development, production, and commercialization of Antibody Drug Conjugates (ADCs). The focus is on understanding the challenges and opportunities at this unique intersection, highlighting how scientific innovation and economic dynamics mutually influence the trajectory of ADCs in the pharmaceutical landscape. RECENT FINDINGS: There has been a significant increase in interest and investment in the development of ADCs. Initially focused on hematological malignancies, ADCs are now being researched for use in treating solid tumors as well. Pharmaceutical companies are heavily investing to broaden the range of indications for which ADCs can be effective. According to a report from the end of 2023, the global ADCs market grew from USD 1.4 billion in 2016 to USD 11.3 billion in 2023, with projections estimating a value of USD 23.9 billion by 2032, growing at a CAGR of 10.7%. ADCs represent a promising class of biopharmaceuticals in oncology, with expanding applications beyond hematological malignancies to solid tumors. The significant growth in the ADC market underscores the impact of scientific and economic factors on their development. This review provides valuable insights into how these factors drive innovation and commercialization, shaping the future of ADCs in cancer treatment.

Mask use among health care workers and feelings of safety at work pre- and post- COVID-19 vaccine.

BACKGROUND: Correct mask use can prevent the spread of COVID-19 and hospitals require correct mask use. Despite this, there is variation in mask use among health care workers (HCW). Incorrect mask use may lead to increased infections and decreased feelings of safety. The purpose of this study was to determine variation in mask use among HCW as well as feelings of safety from exposure to COVID-19 when around colleagues before and after COVID-19 vaccine roll out. METHODS: This study used direct observation to assess mask use in patient-facing areas before and after COVID-19 vaccine. A staff survey was used to assess feelings of safety. RESULTS: Over 1,600 mask observations showed increased compliance from 94.6% to 97.5% (P = .001). Three hundred survey responses showed significantly increased feelings of safety (P < .001) after vaccine roll out, and 203 free-text responses with respondant reasoning were categorized into 6 themes. DISCUSSION: Understanding mask use behaviors and safety attitudes of HCW can help improve policies, workplace culture, and reduce HCW to HCW infections. CONCLUSIONS: Correct mask use was a highly adopted habit in patient-facing areas. The COVID-19 vaccine led to significantly increased feelings of safety among HCW, though the diverging narratives seen in the survey may be helpful to consider when crafting safety interventions.

A dose- and time-controllable syngeneic animal model of breast cancer microcalcification.

The development of novel diagnostic agents for the detection of breast cancer microcalcifications requires a reliable animal model. Based on previous work from our group, we hypothesized that a single systemic injection of recombinant bone morphogenetic protein-2 (rBMP-2) could be used to create such a model. The cDNA encoding mature human BMP-2 was expressed in BL21(DE3) bacteria, purified to homogeneity, and refolded as a dimer. Bioactivity was confirmed using a C2C12 alkaline phosphatase assay. rBMP-2 was radiolabeled with (99m)Tc, and its biodistribution and clearance were quantified after both intravenous (IV) and intraperitoneal (IP) injection. Fischer 344 rats bearing syngeneic R3230 breast tumors received a single intraperitoneal injection of rBMP-2 at a specified dose. Tumor microcalcification was quantified over time using micro-single photon emission computed tomography (SPECT) and microcomputed tomography (CT). rBMP-2 could be expressed in E. coli at high levels, isolated at >95% purity, and refolded to a bioactive dimer. Beta-phase half-life was 30.5 min after IV administration and 47.6 min after IP administration. Renal excretion was the primary mode of clearance. A single IP injection of >or=50 microg rBMP-2 when tumors were not yet palpable resulted in dose-dependent microcalcification in 8 of 8 R3230 tumors. No calcification was found in control tumors or in normal tissues and organs of animals injected with rBMP-2. Tumor calcification increased progressively between weeks 2 and 4 post-rBMP-2 injection. A single IP injection of rBMP-2 in rats bearing a syngeneic breast cancer will produce dose-dependent and time-dependent microcalcifications. This animal model lays the foundation for the development of novel diagnostic radiotracers for breast cancer.

Annexin A2 is a molecular target for TM601, a peptide with tumor-targeting and anti-angiogenic effects.

TM601 is a synthetic form of chlorotoxin, a 36-amino acid peptide derived from the venom of the Israeli scorpion, Leirius quinquestriatus, initially found to specifically bind and inhibit the migration of glioma cells in culture. Subsequent studies demonstrated specific in vitro binding to additional tumor cell lines. Recently, we demonstrated that proliferating human vascular endothelial cells are the only normal cell line tested that exhibits specific binding to TM601. Here, we identify annexin A2 as a novel binding partner for TM601 in multiple human tumor cell lines and human umbilical vein endothelial cell (HUVEC). We demonstrate that the surface binding of TM601 to the pancreatic tumor cell line Panc-1 is dependent on the expression of annexin A2. Identification of annexin A2 as a binding partner for TM601 is also consistent with the anti-angiogenic effects of TM601. Annexin A2 functions in angiogenesis by binding to tissue plasminogen activator and regulating plasminogen activation on vascular endothelial cells. We demonstrate that in HUVECs, TM601 inhibits both vascular endothelial growth factor- and basic fibroblast growth factor-induced tissue plasminogen activator activation, which is required for activation of plasminogen to plasmin. Consistent with inhibition of cell surface protease activity, TM601 also inhibits platelet-derived growth factor-C induced trans-well migration of both HUVEC and U373-MG glioma cells.

Design considerations for tumour-targeted nanoparticles.

Inorganic/organic hybrid nanoparticles are potentially useful in biomedicine, but to avoid non-specific background fluorescence and long-term toxicity, they need to be cleared from the body within a reasonable timescale. Previously, we have shown that rigid spherical nanoparticles such as quantum dots can be cleared by the kidneys if they have a hydrodynamic diameter of approximately 5.5 nm and a zwitterionic surface charge. Here, we show that quantum dots functionalized with high-affinity small-molecule ligands that target tumours can also be cleared by the kidneys if their hydrodynamic diameter is less than this value, which sets an upper limit of 5-10 ligands per quantum dot for renal clearance. Animal models of prostate cancer and melanoma show receptor-specific imaging and renal clearance within 4 h post-injection. This study suggests a set of design rules for the clinical translation of targeted nanoparticles that can be eliminated through the kidneys.

Tissue- and organ-selective biodistribution of NIR fluorescent quantum dots.

A significant portion of the field of nanomedicine is predicated on being able to target nanoparticles to sites of disease. However, in vivo biodistribution and clearance of nanoparticles are poorly understood. In this study, a novel formulation of near-infrared fluorescent InAs(ZnS) quantum dots was synthesized and coated with a systematically increasing chain length of PEG. We found that varying PEG chain length resulted in major changes in organ/tissue-selective biodistribution and clearance from the body.

Multivalent scaffolds for affinity maturation of small molecule cell surface binders and their application to prostate tumor targeting.

Adamantane scaffolds for affinity maturation of prostate cancer specific ligands of low molecular mass are described. These scaffolds are modular and can be used for conjugation of up to three ligands and an additional effector molecule by standard peptide coupling techniques. The potential of the scaffolds is demonstrated with the multimerization of GPI 1, a prostate cancer specific small molecule. A detailed study of multimerized GPI conjugates with near-infrared fluorophores and their binding properties to different prostate cancer cell lines shows the specific binding of these conjugates to cell types positive for prostate specific membrane antigen (PSMA). We demonstrate that these conjugates allow the sensitive imaging of prostate cancer cells with NIR methodology and suggest that our adamantane scaffolds might be generally useful for affinity maturation of small molecules targeting cell surface epitopes.

Detection of breast cancer microcalcifications using a dual-modality SPECT/NIR fluorescent probe.

Efficient chemical synthesis of a trifunctional, hydroxyapatite-binding molecule, which provides simultaneous in vivo imaging by NIR fluorescence and SPECT/CT has been described. Quantitation by SPECT provides the "gold standard" by which NIR fluorescence tomography of breast cancer microcalcifications can now be compared and optimized.

Microwave-assisted synthesis of near-infrared fluorescent sphingosine derivatives.

Microwave-assisted synthesis of near-infrared fluorescent sphingosine derivatives is described, and the utility of the probes demonstrated by co-localization studies with visible wavelength fluorescent sphingosine derivatives.

Quantitation of CXCR4 expression in myocardial infarction using 99mTc-labeled SDF-1alpha.

UNLABELLED: The chemokine stromal-derived factor-1alpha (SDF-1alpha, CXCL12) and its receptor CXCR4 are implicated as key mediators of hematopoietic stem cell retention, cancer metastasis, and HIV infection. Their role in myocardial infarction (MI) is not as well defined. The noninvasive in vivo quantitation of CXCR4 expression is central to understanding its importance in these diverse processes as well in the cardiac response to injury. METHODS: Recombinant SDF-1alpha was radiolabeled under aprotic conditions and purified by gel-filtration chromatography (GFC) using high-specific-activity 99mTc-S-acetylmercaptoacetyltriserine-N-hydroxysuccinimide ([99mTc-MAS3]-NHS) prepared by solid-phase preloading. Radiotracer stability and transmetallation under harsh conditions were quantified by GFC. Affinity, specificity, and maximum number of binding sites (Bmax) were quantified, with adenoviral-expressed CXCR4 on nonexpressing cells and endogenous receptor on rat neonatal cardiomyocytes, using a high-throughput live-cell-binding assay. Blood half-life, biodistribution, and clearance of intravenously injected [99mTc-MAS3]-SDF-1alpha were quantified in Sprague-Dawley rats before and after experimentally induced MI. RESULTS: [99mTc-MAS3]-SDF-1alpha could be prepared in 2 h total with a specific activity of 8.0 x 10(7) MBq/mmol (2,166 Ci/mmol) and a radiochemical purity greater than 98%. Degradation of the radiotracer after boiling for 5 min, with and without 1 mM dithiothreitol, and transmetallation in 100% serum at 37 degrees C for 4 h were negligible. [99mTc-MAS3]-SDF-1alpha exhibits high specificity for CXCR4 on the surface of living rat neonatal cardiomyocytes, with an affinity of 2.7 +/- 0.9 nM and a Bmax of 4.8 x 10(4) binding sites per cell. After intravenous injection, 99mTc-labeled SDF-1alpha displays a blood half-life of 25.8 +/- 4.6 min, rapid renal clearance with only 26.2 +/- 6.1 percentage injected dose remaining in the carcass at 2 h, consistently low uptake in most organs (<0.1 percentage injected dose per gram), and no evidence of blood-brain barrier penetration. After MI was induced, CXCR4 expression levels in the myocardium increased more than 5-fold, as quantified using [99mTc-MAS3]-SDF-1alpha and confirmed using confocal immunofluorescence. CONCLUSION: We describe a 99mTc-labeled SDF-1alpha radiotracer that can be used as a sensitive and specific probe for CXCR4 expression in vivo and demonstrate that this radiotracer is able to quantify changes in CXCR4 expression under different physiologic and pathologic states. Taken together, CXCR4 levels should now be quantifiable in vivo in a variety of animal model systems of human diseases.

Water-soluble fullerene (C60) derivatives as nonviral gene-delivery vectors.

A new class of water-soluble C60 transfecting agents has been prepared using Hirsch-Bingel chemistry and assessed for their ability to act as gene-delivery vectors in vitro. In an effort to elucidate the relationship between the hydrophobicity of the fullerene core, the hydrophilicity of the water-solubilizing groups, and the overall charge state of the C60 vectors in gene delivery and expression, several different C60 derivatives were synthesized to yield either positively charged, negatively charged, or neutral chemical functionalities under physiological conditions. These fullerene derivatives were then tested for their ability to transfect cells grown in culture with DNA carrying the green fluorescent protein (GFP) reporter gene. Statistically significant expression of GFP was observed for all forms of the C60 derivatives when used as DNA vectors and compared to the ability of naked DNA alone to transfect cells. However, efficient in vitro transfection was only achieved with the two positively charged C60 derivatives, namely, an octa-amino derivatized C60 and a dodeca-amino derivatized C60 vector. All C60 vectors showed an increase in toxicity in a dose-dependent manner. Increased levels of cellular toxicity were observed for positively charged C60 vectors relative to the negatively charged and neutral vectors. Structural analyses using dynamic light scattering and optical microscopy offered further insights into possible correlations between the various derivatized C60 compounds, the C60 vector/DNA complexes, their physical attributes (aggregation, charge) and their transfection efficiencies. Recently, similar Gd@C60-based compounds have demonstrated potential as advanced contrast agents for magnetic resonance imaging (MRI). Thus, the successful demonstration of intracellular DNA uptake, intracellular transport, and gene expression from DNA using C60 vectors suggests the possibility of developing analogous Gd@C60-based vectors to serve simultaneously as both therapeutic and diagnostic agents.

Renal clearance of quantum dots.

The field of nanotechnology holds great promise for the diagnosis and treatment of human disease. However, the size and charge of most nanoparticles preclude their efficient clearance from the body as intact nanoparticles. Without such clearance or their biodegradation into biologically benign components, toxicity is potentially amplified and radiological imaging is hindered. Using intravenously administered quantum dots in rodents as a model system, we have precisely defined the requirements for renal filtration and urinary excretion of inorganic, metal-containing nanoparticles. Zwitterionic or neutral organic coatings prevented adsorption of serum proteins, which otherwise increased hydrodynamic diameter by >15 nm and prevented renal excretion. A final hydrodynamic diameter <5.5 nm resulted in rapid and efficient urinary excretion and elimination of quantum dots from the body. This study provides a foundation for the design and development of biologically targeted nanoparticles for biomedical applications.

Production of multimeric prostate-specific membrane antigen small-molecule radiotracers using a solid-phase 99mTc preloading strategy.

UNLABELLED: Small-molecule ligands specific for prostate-specific membrane antigen (PSMA) have the potential to improve prostate cancer imaging. However, highly charged ligands are difficult to label with 99mTc and to purify. In this study, we present an adamantane-trimerized small molecule that has nanomolar binding to PSMA and also has 12 negative charges. METHODS: To convert this molecule into a clinically viable SPECT diagnostic, we have developed a simple, cartridge-based, solid-phase prelabeling strategy that, within 25 min, converts readily available and inexpensive 99mTc-pertechnetate into a chemically pure complex, with a reactive N-hydroxysuccinimide (NHS) ester, in neat organic solvent. This stable intermediate can label any amine-containing small molecule or peptide with 99mTc in 1 step, with high specific activity and without the need for high-performance liquid chromatography (HPLC). RESULTS: Solid-phase conversion of 99mTc-pertechnetate to 99mTc-MAS3-NHS (MAS3 is S-acetylmercaptoacetyltriserine) could be completed in 25 min, with >99% radiochemical purity and with no coligands present. This intermediate was then conjugated to adamantane-trimerized GPI (2[(3-amino-3-carboxypropyl)(hydroxy)(phosphinyl)-methyl]pentane-1,5-dioic acid) in 1 step with >95% yield and no need for HPLC purification. The final molecule bound specifically to living human tumor cells expressing PSMA on their surface. Quantitative comparison was made among GPI monomer, GPI trimer, and their 99mTc-derivatives. CONCLUSION: Our study describes a simple cartridge-based conversion of 99mTc-pertechnetate to a useful, preloaded NHS ester intermediate that takes only 25 min to prepare and results in >99% radiochemical purity. Using this chemistry, we produced a high-specific-activity, 99mTc-labeled, PSMA-targeted small molecule and demonstrate gamma-ray radioscintigraphic imaging of living human prostate cancer cells.

An HPLC/mass spectrometry platform for the development of multimodality contrast agents and targeted therapeutics: prostate-specific membrane antigen small molecule derivatives.

The production of disease-targeted agents requires the covalent conjugation of a targeting molecule with a contrast agent or therapeutic, followed by purification of the product to homogeneity. Typical targeting molecules, such as small molecules and peptides, often have high charge-to-mass ratios and/or hydrophobicity. Contrast agents and therapeutics themselves are also diverse, and include lanthanide chelates for MRI, (99m)Tc chelates for SPECT, (90)Y chelates for radiotherapy, (18)F derivatives for PET, and heptamethine indocyanines for near-infrared fluorescent optical imaging. We have constructed a general-purpose HPLC/mass spectrometry platform capable of purifying virtually any targeted agent for any modality. The analytical sub-system is composed of a single dual-head pump that directs mobile phase to either a hot cell for the purification of radioactive agents or to an ES-TOF MS for the purification of nonradioactive agents. Nonradioactive agents are also monitored during purification by ELSD, absorbance and fluorescence. The preparative sub-system is composed of columns and procedures that permit rapid scaling from the analytical system. To demonstrate the platform's utility, we describe the preparation of five small molecule derivatives specific for prostate-specific membrane antigen (PSMA): a gadolinium derivative for MRI, indium, rhenium and technetium derivatives for SPECT, and an yttrium derivative for radiotherapy. All five compounds are derived from a highly anionic targeting ligand engineered to have a single nucleophile for N-hydroxysuccinimide-based conjugation. We also describe optimized column/mobile phase combinations and mass spectrometry settings for each class of agent, and discuss strategies for purifying molecules with extreme charge and/or hydrophobicity. Taken together, our study should expedite the development of disease-targeted, multimodality diagnostic and therapeutic agents.