#gemtuzumab

[impomed]

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[scottfeldberg]

Guidelines for Chemotherapy Administration Codes

Basics of Chemotherapy Administration Codes Before having detailed understanding about guidelines for chemotherapy administration codes, let’s define chemotherapy. Chemotherapy is a treatment of disease by means of chemical substances or drugs; usually used in reference to neoplastic disease. Procedure (CPT) code range 96401 to 96542, and 96549 cover chemotherapy administration. Medicare also identifies CPT codes 0662T and 0663T which are considered incidental to the professional charges for chemotherapy administration where no separate payment will be made. Services and items like use of local anesthesia; IV access; access to indwelling IV, subcutaneous catheter or port; flush at conclusion of infusion; standard tubing, syringes and supplies; and preparation of chemotherapy agent(s) are included chemotherapy and are not separately billable. Payment for the above is included in the payment for the chemotherapy administration service.

Chemotherapy administration codes apply to parenteral administration of non-radionuclide anti-neoplastic drugs; and also to anti-neoplastic agents provided for treatment of non-cancer diagnoses (e.g., cyclophosphamide for auto-immune conditions) or to substances such as monoclonal antibody agents, and other biologic response modifiers. Chemotherapy administration codes are used for services of a physician or qualified assistant employed by and under the supervision of a physician. Infliximab, rituximab, alemtuzumb, gemtuzumab, and trastuzumab drugs are commonly considered to fall under the category of monoclonal antibodies. Drugs commonly considered to fall under the category of hormonal ant-ineoplastics include leuprolide acetate and goserelin acetate.

Guidelines for Chemotherapy Administration (Non-chemotherapy Injections and Infusion Services) When administering multiple infusions, injections or combinations, the physician should report only one ‘initial’ service code unless protocol requires that two separate IV sites must be used. The initial code is the code that best describes the key or primary reason for the encounter and should always be reported irrespective of the order in which the infusions or injections occur. If an injection or infusion is of a subsequent or concurrent nature, even if it is the first such service within that group of services, then a subsequent or concurrent code should be reported. For example, the first IV push given subsequent to an initial one-hour infusion is reported using a subsequent IV push code. If more than one ‘initial’ service code is billed per day, the payer might deny the second initial service code unless the patient has to come back for a separately identifiable service on the same day or has two IV lines per protocol. For these separately identifiable services, instruct the physician to report with modifier 59. The CPT includes a code for a concurrent infusion in addition to an intravenous infusion for therapy, prophylaxis or diagnosis. Allow only one concurrent infusion per patient per encounter. Do not allow payment for the concurrent infusion billed with modifier 59 unless it is provided during a second encounter on the same day with the patient and is documented in the medical record. The physician may report the infusion code for ‘each additional hour’ only if the infusion interval is greater than 30 minutes beyond the 1 hour increment. For example if the patient receives an infusion of a single drug that lasts 1 hour and 45 minutes, the physician would report the “initial” code up to 1 hour and the add-on code for the additional 45 minutes. Several chemotherapy administration and non-chemotherapy injection and infusion service codes have the following parenthetical descriptor included as a part of the CPT code, ‘List separately in addition to code for primary procedure.’ Each of these codes has a physician fee schedule indicator of ‘ZZZ’ meaning this service is allowed if billed with another chemotherapy administration or non-chemotherapy injection and infusion service code. Do not interpret this parenthetical descriptor to mean that the add-on code can be billed only if it is listed with another drug administration primary code. For example, code 90761 will be ordinarily billed with code 90760. However, there may be instances when only the add-on code, 90761, is billed because an “initial” code from another section in the drug administration codes, instead of 90760, is billed as the primary code. If there is a visit or other chemotherapy administration or non-chemotherapy injection or infusion service provided on the same day, payment for 96523 is included in the payment for the other service. Coding team and physicians should follow the CPT coding instructions to report chemotherapy administration and non-chemotherapy injections and infusion services with the exception listed in subsection C for CPT code 90772. Guidelines for Chemotherapy Administration and E/M Services Furnished on the Same Day Physicians providing a chemotherapy administration service or a non-chemotherapy drug infusion service and evaluation and management services (other than CPT code 99211), on the same day must bill using modifier 25. The insurance carrier might pay for evaluation and management services provided on the same day as the chemotherapy administration services or a non-chemotherapy injection or infusion service if the evaluation and management service meets the requirements of section §30.6.6 even though the underlying codes do not have global periods. If a chemotherapy service and a significant separately identifiable evaluation and management service are provided on the same day, a different diagnosis is not required. While billing for chemotherapy note that, The administration of anti-anemia drugs and anti-emetic drugs by injection or infusion for cancer patients is not considered chemotherapy administration. When billing a dosage higher than that listed in the HCPCS Manual, use the units field to indicate a higher dosage. For example: The common dosage for J9070 is 100 mg. but 490 mg. was administered. Submit five units of service (round up the dosage). Professional charges 96360-96379 (infusion/injection services), 96521-96523 (pump refills/maintenance) and codes for chemotherapy administration codes 96401-96425 should not be submitted when services are administered in hospital or home setting. If a significant separately identifiable evaluation and management service is performed, the appropriate E & M code should be reported utilizing modifier 25 in addition to the chemotherapy code. For an evaluation and management service provided on the same day, a different diagnosis is not required. Legion Healthcare Solutions is a leading medical billing company providing complete billing and coding services. We referred ‘Medicare Claims Processing Manual Chapter 12’ to discuss guidelines for chemotherapy administration codes. If you need any assistance in oncology medical billing and coding services, contact us at 727-475-1834 or email us at info@legionhealthcaresolutions.com

[medchemexpressinhibitor-blog]

Antibody — Drug Conjugates (ADCs), a Growing Class of Targeted Cancer Therapeutics

Despite of disappointing clinical results and withdraw for the first antibody-drug conjugate (ADC) Gemtuzumab ozogamicin, tremendous ADC development on modification and optimization has been attempted to improve clinical efficacy and minimize toxicity. After decades of dynamic research, these efforts are now bearing fruit with about a dozen of new ADC approvals in the past 10 years (Table 1). In 2017, a lower and fractionated dose of Gemtuzumab ozogamicin was approved too. Most recently, the phenomenal clinical results of Trastuzumab deruxtecan used in the treatment of previously treated HER2-low advanced breast cancer ignite more enthusiasm in the field and will certainly boost exponential research and growth in the development of ADCs for more approvals.DrugMakerIndicationsTrade nameTarget AntigenApproval Year

Gemtuzumab ozogamicinPfizer/WyethRelapsed acute myelogenous leukemia (AML)MylotargCD332017;2000

Brentuximab vedotinSeattle Genetics, Millennium/TakedaRelapsed HL and relapsed sALCLAdcetrisCD302011

Trastuzumab emtansineGenentech, RocheHER2-positive metastatic breast cancer (mBC) following treatment with trastuzumab and a maytansinoidKadcylaHER22013

Inotuzumab ozogamicinPfizer/WyethRelapsed or refractory CD22-positive B-cell precursor acute lymphoblastic leukemiaBesponsaCD222017

Moxetumomab pasudotoxAstrazenecaAdults with relapsed or refractory hairy cell leukemia (HCL)LumoxitiCD222018

Polatuzumab vedotin-piiqGenentech, RocheRelapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL)PolivyCD792019

Enfortumab vedotinAstellas/Seattle GeneticsAdult patients with locally advanced or metastatic urothelial cancer who have received a PD-1 or PD-L1 inhibitor, and a Pt-containing therapyPadcevNectin-42019

Trastuzumab deruxtecanAstraZeneca/Daiichi SankyoAdult patients with unresectable or metastatic HER2-positive breast cancer who have received two or more prior anti-HER2 based regimensEnhertuHER22019

Sacituzumab govitecanImmunomedicsAdult patients with metastatic triple-negative breast cancer (mTNBC) who have received at least two prior therapies for patients with relapsed or refractory metastatic diseaseTrodelvyTrop-22020

Belantamab mafodotin-blmfGlaxoSmithKline (GSK)Adult patients with relapsed or refractory multiple myelomaBlenrepBCMA2020

Loncastuximab tesirine-lpylADC TherapeuticsLarge B-cell lymphomaZynlontaCD192021

Tisotumab vedotin-tftvSeagen IncRecurrent or metastatic cervical cancerTivdakTissue factor2021

Table 1. FDA-approved ADC drugs

The concept of ADC can be traced back to the early 1900s, when German physician and scientist Paul Ehrlich proposed a visionary “magic bullet” that could deliver a toxic drug to certain malignant cells without affecting other normal tissues.

In the second half of last century, advances in chemistry for the linkage between cytotoxic agents and antibodies, as well as new techniques in hybridoma technology enabling the production of homogenous and target-accurate mAbs, led to the generation of ADCs with promising results. Now at a seemingly golden age of ADC drug development, the global market sales for ADC drugs are projected to exceed $ 16.4 billion in the next five years.[1] A scheme of the brief history of ADC development is shown in Fig 1 and the structures of some selected FDA-approved ADCs are listed in Fig 2.

Figure 1. Brief History of ADC development

[2]

Figure 2. Structures of selected FDA-approved ADCs

[3]

(Orange: cytotoxin agents; blue: linkers; purple: antibodies)Structure and Mechanism of Action of ADC

Different from traditional chemotherapeutics, all ADCs consist of three core components: a monoclonal antibody that can binds to a tumor-associated antigen, a cytotoxic agent (payload) and a cleavable or uncleavable linker that covalently connects antibody and payload. After ADC enters blood circulation system, the antibody component of ADC recognizes and binds to the cell-surface antigens on the targeted cancer cells. Upon internalization of the ADC-antigen complex through endocytosis, payload component is released into cytosol after cleavage by lysosome degradation pathway. The released bioactive payload binds to its targets, resulting in cancer cell death. [4]

The targeted delivery cytotoxic payload by ADC is expected to increase payload concentration in tumor cells, thus minimizing the required effective dose. The therapeutic window is narrow for early ADCs due to their off-target toxicity linked to unstable conjugation, competition with unconjugated antibody, and aggregation or fast clearance of conjugates. Although the basic approach of design and construction of ADCs remain constant, the selection of three components significantly affects the pharmacokinetic, pharmacodynamic, and clinical outcomes among different ADCs.

The latest developments in new payload discovery, linker optimization, antibody engineering, and advances of conjugation chemistry have led to the third generation of ADCs with improved therapeutic window (Fig 3).

Figure 3. Therapeutic window of ADCs

[5]

Target Antigen Selection

The features of an ideal target antigen includes: 1) Predominantly expressed on the surface of target tumor cells with limited heterogeneity compared to normal tissues; 2) Minimal antigen shedding to avoid antibody binding within the circulation; 3) Well internalizing ADC through receptor-mediated endocytosis and should not be modulated during endocytosis; 4) Antigen levels remain constant after ADC treatment.

Target antigens in stroma and vasculature in solid tumor is another approach. Additionally, targeting antigens in cancer stem cells has also been investigated.

Figure 4. Target antigens for ADCs in solid tumors

[6]

Selection of AntibodiesThe antibody component of ADC functions as a vehicle, responsible for selectively delivering the cytotoxic payload to the target cancer cells.

Ideal antibodies have high specificity and affinity to tumor associated antigens, good stability, low immunogenicity, low cross reaction, long circulating half-life, and efficient internalization

. Currently, human IgG isotypes, particularly IgG1, are predominantly used as antibody backbone in the construction of ADCs. Four subtypes of human IgG differ in their constant domains and hinge regions with different solubility and half-life as well as their different affinity for Fcγ receptors (FcγR) expressed on immune effector cells (Fig 5).

Figure 5. Summary of IgG subtypes for potential use in ADCs

[3]

Selection of Payloads

Studies have shown that only a small fraction of cytotoxic payload with about 1-2% of administered dose can reach the tumor cells. Therefore, high potency of cytotoxic payloads is required to achieve therapeutic efficacy, with IC50 in sub-nanomolar or picomolar range (Fig 6). Payloads are normally small molecules and exert their activity by binding to intracellular targets (Fig 7).

Other favorable features of desired payloads include acceptable aqueous solubility, sufficient stability as conjugates, low immunogenicity, and a long half-life. The payload should retain its potency when modified for linkage. In addition to prevention of antibody aggregation and clearance, a balanced hydrophobic/hydrophilic physicochemical property of payload could lead to bystander effects on killing surrounding cells.

Figure 6. Potency of selected payloads

[7]

Figure 7. Payloads for ADC drugs

[8]

Selection of ADC Linkers

The linkers covalently tethering antibody and payload moieties play critical roles in the control of pharmacokinetic and pharmacodynamic (PK/PD) properties, therapeutic window, and ultimately the efficacy of ADC. The linkers should be metabolically stable in blood, thus preventing premature cleavage and ensuring sufficient delivery of ADC to the target tumor cells. Furthermore, a desired linker is able to facilitate rapid release of free and cytotoxic payload after internalization of ADC inside the tumor cells. The linkers with calibrated hydrophobicity possess capabilities to induce bystander effects for ADC to kill additional tumor cells in vicinity, irrespective of the expression of the target antigens on their surface. Therefore, linkers consist of three moieties: a suitable functional group for conjugating to the antibody, a spacer unit containing hydrophilic elements, and a trigger for releasing the cytotoxic payload.

There are two types of linkers: cleavable and non-cleavable. Cleavable linkers can be divided into acid cleavable, reducible and protease cleavable. The most frequently used linkers are maleimidocaproyl (MC), N-succinimidyl 4-(maleimidomethyl) cyclohexane-1-carboxylate (SMCC), N-succinimidyl-4-(2-pyridyldithio) butanoate (SPDB), N-succinimidyl-4-(2-pyridyldithio) pentanoate (SPP), peptides, hydrazones, and disulfides.

Figure 8. Comparison of different linkers

[9]

Figure 9. Cleavage of linkers

[8]

Conjugation for ADC Construction

The stoichiometry of the linker-payloads on the antibody (drug-to-antibody ratio, DAR) is an important factor for the efficacy and safety profile of the ADC. Since most payloads are hydrophobic species. High DAR with too many payloads attached to the antibody will cause an increase in protein aggregation, ADC clearance in blood, and off-target side effects. A controlled and homogenous DAR should be optimized with maximized PK/PD profile, safety, and efficacy. Novel approaches using site-specific conjugation (SSC) aim to minimize heterogeneity and produce more homogenous ADCs, thus expanding therapeutic window. These controlled conjugation strategies include engineered cysteine residues, unnatural amino acids, and enzymatic conjugation through glycotransferases and transglutaminases.

Selection of the attachment site of linker-payload to the antibody is also crucial. The selected site should not interfere antibody-antigen binding and leave internalization process unaffected. Additionally, the attachment site could have an impact on linker stability, subsequently affecting drug release rate.

Figure 10. The therapeutic effects of DAR and attachment sites on ADCs

[3]

Summary and ProspectiveA widespread interest in the development of ADC drugs for targeted cancer treatment in the past decade has led to a dozen of FDA-approved ADC drugs. Extensive research on selection of antigen targets and payloads, antibody engineering, linker optimization, and conjugation chemistry enable the construction of homogenous, effective, and safe ADCs with wider therapeutic windows. The rapid growth of ADC development warrants more innovative ADCs in the near future.Strength of MCE ServicesWe have extensive experiences in research and development of ADC products. Having strong technical teams and state-of-the-art instruments, MCE is proud to partner with clients including academic research laboratories and international pharmaceutical companies, such as Abbie and AstraZeneca. Efficient and prompt services with high-quality products are guaranteed.

Wide-Range of Diversified ProductsWith breakthroughs and innovations on payload synthesis, diversified linkers, and conjugation chemistry, we offer customer synthesis of the most comprehensive, integrated portfolio of ADC products in response to clients’ needs. MCE serves global customers with 1000+ ADC related products.

One-stop Services for ADCsWith strong teams of experienced biochemists, synthetic and analytical chemists, MCE can provide one-stop services for the design, synthesis, analysis, purification, optimization, detection, and evaluation of ADC-related products (antibodies, payloads, linkers, drug-linker conjugates, and ADC drugs).

Related ProductsProduct NameDescription

ADC Cytotoxin

Mertansine (DM1)

A microtubulin maytansinoid inhibitor. To overcome systemic toxicity and enhance tumor-specic delivery.

Calicheamicin

An antitumor antibiotic. A DNA synthesis inhibitor. To cause double-strand DNA breaks.

ADC Linker

MC-Val-Cit-PAB

A cathepsin cleavable ADC linker that is used for making antibody-drug conjugate.

SMCC

A non-cleavable ADC linker that is used for making antibody-drug conjugate.

Drug-Linker Conjugates for ADC

SMCC-DM1 (DM1-SMCC)

SMCC-DM1 (DM1-SMCC) is a drug-linker conjugate composed of a potent microtubule-disrupting agent DM1 and an SMCC linker to make antibody drug conjugate (ADC).

MC-Val-Cit-PAB-duocarmycin

MC-Val-Cit-PAB-duocarmycin is a drug-linker conjugate for ADC with potent antitumor activity using Duocarmycin (a DNA minor groove binding alkylating agent), connected via the ADC linker MC-Val-Cit-PAB.

Antibody-drug Conjugates (ADCs)

Trastuzumab emtansine

Trastuzumab emtansine (Ado-Trastuzumab emtansine) is an antibody-drug conjugate (ADC) that incorporates the HER2-targeted antitumor properties of trastuzumab with the cytotoxic activity of the microtubule-inhibitory agent DM1 (derivative of maytansine).

Trastuzumab deruxtecan

Trastuzumab deruxtecan (DS-8201a) is an anti-human epidermal growth factor receptor 2 (HER2) antibody-drug conjugate (ADC). Trastuzumab deruxtecan is composed of a humanized anti-HER2 antibody, an enzymatically cleavable peptide-linker, and a topoisomerase I inhibitor. References

References[1]. do Pazo C, Nawaz K, Webster RM, et al. The oncology market for antibody-drug conjugates. Nat Rev Drug Discov. 2021 Aug;20(8):583-584.

[2]. David E Thurston, Paul J M Jackson, et al. Cytotoxic Payloads for Antibody–Drug Conjugates[M]. The Royal Society of Chemistry, 2019.

[3]. Walsh SJ, Bargh JD, Dannheim FM, Hanby AR, Seki H, Counsell AJ, Ou X, Fowler E, Ashman N, Takada Y, Isidro-Llobet A, Parker JS, Carroll JS, Spring DR. Site-selective modification strategies in antibody-drug conjugates. Chem Soc Rev. 2021 Jan 21;50(2):1305-1353.

[4]. Chau CH, Steeg PS, Figg WD, et al. Antibody-drug conjugates for cancer. Lancet. 2019 Aug 31;394(10200):793-804.

[5]. Beck A, Goetsch L, Dumontet C, Corvaïa N, et al. Strategies and challenges for the next generation of antibody-drug conjugates. Nat Rev Drug Discov. 2017 May;16(5):315-337.

[6]. Diamantis N, Banerji U, et al. Antibody-drug conjugates--an emerging class of cancer treatment. Br J Cancer. 2016 Feb 16;114(4):362-7.

[7]. Nakada T, Sugihara K, Jikoh T, Abe Y, Agatsuma T, et al. The Latest Research and Development into the Antibody-Drug Conjugate, [fam-] Trastuzumab Deruxtecan (DS-8201a), for HER2 Cancer Therapy. Chem Pharm Bull (Tokyo). 2019;67(3):173-185.

[8]. Drago JZ, Modi S, Chandarlapaty S, et al. Unlocking the potential of antibody-drug conjugates for cancer therapy. Nat Rev Clin Oncol. 2021 Jun;18(6):327-344.

[9]. Tsuchikama K, An Z, et al. Antibody-drug conjugates: recent advances in conjugation and linker chemistries. Protein Cell. 2018 Jan;9(1):33-46.

[ladyespera]

hang on these are just star wars character names

[ptmasterguide]

Gemtuzumab Ozogamicin (Mechanism of Action)

Gemtuzumab Ozogamicin (Mechanism of Action)

In this article, we will discuss Gemtuzumab Ozogamicin (Mechanism of Action). So, let’s get started. Mechanism of ActionGemtuzumab ozogamicin is a CD33-directed antibody-drug conjugate (ADC). The antibody portion (hP67.6) recognizes human CD33 antigen. The small molecule, N-acetyl gamma calicheamicin, is a cytotoxic agent that is covalently attached to the antibody via a linker. Nonclinical data…

[candyswift-ny]

CD33-targeted Bispecific Antibodies: An Emerging Therapy for Acute Myeloid Leukemia

Acute myeloid leukemia (AML) is a genetically heterogeneous disease characterized by the clonal expansion of leukemic cells. Despite a better understanding of the biology of AML and the recent approval of new drugs for AML, the 5-year overall survival rate of standard cytotoxic chemotherapy is still only 30%, and new therapies are urgently needed.

In recent years, T-cell-based immunotherapy has received much attention as a promising immunotherapeutic approach for the treatment of various malignancies. AML infected cells are highly sensitive to the cytotoxic effects of functional immune cells, and bispecific T-cell designs provide an effective means of treatment for AML.

CD33 is a sialic acid-binding Ig-like lectin (Siglec) expressed as a 67-kd glycosylated transmembrane protein on normal pluripotent stem-like precursor cells, monopotent stem cells, mature granulocytes, and monocytes. It is also present on macrophages, dendritic cells and can be expressed on B-cell subsets, activated T cells and natural killer cells.

CD33 is expressed on the surface of more than 80% of AML isolates with a high average antigenic density. The differential expression of CD33 on the surface of malignant AML cells makes it an ideal target for immunotherapy. The best-known clinical CD33-targeted immunotherapy is the anti-CD33 antibody gemtuzumab ozogamicin (GO), which was approved in 2000 for the treatment of first relapsed CD33+ AML patients over 60 years of age, but was voluntarily withdrawn from the market due to lack of clinical benefit and increased adverse events. However, GO was reapproved in 2017 after further studies at that time showed benefit from adding GO in fractional doses to standard chemotherapy.

A number of immunotherapies targeting CD33, including ADCs, CAR-T cells and bispecific antibodies, are currently being evaluated in the clinic or are in preclinical development. Four CD33 bispecific antibodies are currently being evaluated in phase I clinical trials.

AMG330 is a short-acting BiTE molecule. Preclinical studies have shown that the anti-CD33 x anti-CD3 structure of the BiTE model is cytotoxic even with a low level of CD33 antigen densities on target cells, making it a candidate for targeting a broad range of CD33+ leukemias, including AML.

AMG673 is a half-life extended BiTE structure that combines the binding specificity of CD33 and CD3, which are fused to the N terminus of a single IgGFc region.

AMV564 is a tetravalent anti-CD33xCD3 TandAb (tandem diabody) structure. Preclinical in vitro and in vivo studies have demonstrated the ability of AMV564 to induce potent cytotoxicity in a dose-dependent manner in CD33+ AML cell lines.

JNJ-67561244 is a fully human IgG4-PAA bispecific antibody that binds the C2 structural domain of CD33 and CD3 to induce T cell recruitment and tumor cytotoxicity. It specifically binds CD33-expressing cells and mediates specific in vitro T cell-dependent cytotoxicity.

With the clinical success of blinatumomab in hematologic oncology, a number of bispecific antibodies targeting the AML-associated antigen CD33 have entered clinical development. To date, the primary serious toxicity of bispecific antibodies targeting CD33 has been cytokine release syndrome (CRS), and mitigation strategies are currently being evaluated. Future trials may well test the combination of bispecific antibodies with other forms of immunotherapy, such as co-stimulation of signaling pathways and targeting of immune evasion mechanisms, to further improve the efficacy and clinical benefit of these treatments.

[impomed]

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[juniperpublishersna]

Bioconjugation among Metallopharmaceuticals: A Review-Juniper Publishers

JUNIPER PUBLISHERS-OPEN ACCESS JOURNAL OF DRUG DESIGNING & DEVELOPMENT

Abstract

This review pertains to an effort to notify the importance of metal binding of naturally occurring molecules. Metallopharmaceutical science is a huge discipline of multifarious applications. In due course of design of metallic drugs one has to rely upon biological relevance of the compound. Sometimes the target activity is lost into toxicity. Hence, the association of a biomolecule or modified bio-compound coordinated with metallic system is the essence of bioconjugation and is the need of hour. Bio-conjugated metallic complexes are always praised for better action. Some diseases have been exemplified in this review and a comprehensive way of presentation has been established throughout the text.

Keywords:  Bioconjugation; AD; Diabetes; Cancer; Antioxidant   

Introduction

Bioconjugation is a meticulous chemical strategy to form a stable covalent link between two molecules, at least one of which is a biomolecule. Synthesis of bioconjugates involves a variety of challenges, ranging from the simple and nonspecific use of a fluorescent dye marker to the complex design of antibody drug conjugates. Antibody-drug conjugates such as Brentuximab vedotin and Gemtuzumab ozogamicin are examples of bioconjugation, and are an active area of research in the pharmaceutical industry [1]. A promising strategy to enable the use of metal nuclides in antibody-targeted imaging and therapy is to design molecules that coordinate to the metal ion and preclude its release in-vivo [2].

A necessary prerequisite of any ligand that binds a metal to form a contrast agent is that the resulting contrast agent be stable so as to prevent the loss of the metal and its subsequent accumulation in the body. Other considerations include an ability to reversibly bind water, which in turn increases it contrastability and decreases the dose level required. This ability is clearly important since the interaction between any two nuclear spins through space decreases at a rate equal to the reciprocal of the distance raised to the sixth power [3].

Hence, metals in medicine are used in organic systems for diagnostic and treatment purposes. Inorganic elements are also essential for organic life as cofactors in enzymes called metalloproteins. When metals are scarce or high quantities, equilibrium is set out of balance and must be returned to its natural state via interventional and natural methods. Metals play a vital role in an immense number of extensively differing biological processes. Some of these processes are quite specific in their metal ion requirements, in that only certain metal ions in specified oxidation states can accomplish the necessary catalytic structural requirement (Figure 1) [4].

One of the principal themes of bioinorganic chemistry is the synthesis of metal complexes that have the ability to mimic the functional properties of natural metalloproteins [5,6]. Proteins, some vitamins and enzymes contain metal ions in their structure involving macromolecular ligands. Inorganic and bioinorganic chemistry are the major contributing fields of medical science and human health witnessed by the past half century. Today, metal-containing therapeutics constitutes a multi-billion dollar industry. Recent investigations in bioinorganic chemistry include the use of metal ions as synthetic scaffolds for the preparation of small molecule therapeutics.   

Insulin Mimicry via Metallic Compounds

In a continued interest towards metallopharmaceuticals (Figure 2) Sodium vanadate and derivatives of bismaltolato- oxovanadium (IV) complexes (BMOV) have been reported to lower levels of blood sugar in diabetic patients [7]. In other words it may be said that scientific community is busy with copying a hormone called as insulin to develop an ultimate treatment of diabetes. Recent under trial experiments with Gold and Silver based glucose level stabilizing agents have further unfurled seek for more efficacy [8,9].

Antidiabetic drugs may be either insulin injections which are used in serious cases of diabetes or oral hypoglycemic drugs, and are suitable for most adult patients. Different hypoglycemic drugs are available in market. These drugs may be classified as the following: Sulphonylureas: increase insulin secretion and help to reduce blood glucose levels. But sulphonylurea may cause weight gain, hypoglycemia and allergic reactions. They are contraindicated in case of pregnancy, lactation and diabetes type 1. They act by affecting the pancreatic β-cells stimulates the movement of insulin-containing secretory granules to the cell surface then into circulation. Biguanides (metformin): They prevent production of glucose in the liver, so improve the body's sensitivity to insulin. They may cause temporary nausea and/or diarrhea, loss of appetite and metallic taste. They are contraindicated with kidney or liver diseases and heart problems. Alpha Glucosidase Inhibitor (Acarbose): They may cause diarrhea, gas, constipation, or stomach pain. Hence, the search for more intelligent/efficient antihyperglycemic or antihypoglycemic agents continues. Dissemination of such area of research expects clinically approved use of metal containing compounds for identifying new medicinal agents from throughout the periodic table to be used as antidiabetic and antioxidant tools.   

Biotransformation of Metallic Compounds

Elemental Medicine is nowadays accepted as a rapidly developing field busy with developing novel therapeutic and diagnostic metal complexes. Advances in biotransformation of metal complexes and targeting, with particular reference to platinum anticancer, gold anti-arthritic, and bismuth antiulcer drugs has remained active goal since decades [10,11]. Studies of iron and copper complexes have shown that they can be more active in cell destruction as well as in the inhibition of DNA synthesis, than the uncomplexed organic ligands [12]. Hence, the field of inorganic chemistry in medicine may usefully be divided into two main categories: firstly, ligands as drugs which target metal ions in some form, whether free or protein- bound; and secondly, metal-based drugs and imaging agents where the central metal ion is usually the key feature of the mechanism of action [13,14]. In addition to metal complexes of novel ligands, compounds of metals with already known organic pharmaceuticals like aspirin, paracetamol, metformin, etc. have gained keen interest [15]. It has been seen that their biological relevance increases on complexing with the respective ligands (organic medicinal chelates). Research has shown significant progress in utilization of transition metal complexes as drugs to treat several human diseases like carcinomas, lymphomas, infection control, anti-inflammatory, diabetes, and neurological disorders [16].

Cancer is the second most frequent cause of death in the world. The discovery of antitumor activity of cisplatin began a search for other metal complexes with cytotoxic properties against cancer cells [17]. The instant information regarding anticancer activities of the ten most active metals: arsenic, antimony, bismuth, gold, vanadium, iron, rhodium, titanium, gallium and platinum have been already updated. Despite the efficacy of cancer treatment using cisplatin, the use is still limited due to severe side effects such as neuro-, hepato- and nephro-toxicity and by resistance phenomena [18]. Gold (III)-dithiocarbamato complexes have recently gained increasing attention as potential anticancer agents because of their strong tumor cell growth- inhibitory effects, generally achieved by exploiting non-cisplatin- like mechanisms of action [19].

The potential applications of Mo-based complexes in medicinal chemistry as metallopharmaceuticals in treating diseases such as cancer and tumors [20] indicate the emphasis of significant approach of non-platin anticancer agents. Ruthenium compounds are highly regarded as potential drug candidates. The compounds offer the potential of reduced toxicity and can be tolerated in-vivo. The various oxidation states, different mechanism of action, and the ligand substitution kinetics of ruthenium compounds give them advantages over platinum- based complexes, thereby making them suitable for use in with promising cytotoxic profiles [21]. The role of transition metals as micronutrients as well as co-factors of several metallo- enzymes in living systems further corroborates the rationale behind synthesis and evaluation of novel transition-metal based complexes for their anticancer effects [22]. Future use of substituted organic ligands and their metal complexes would hence bring forth effective anticancer agents and would depend on structural modifications as would afford them better potency against a number of tumors/cancers, together with low toxicity and better solubility.   

Antioxidant Properties of Metal Complexes

An antioxidant is a molecule that inhibits the oxidation of other molecules. Oxidation is a chemical reaction that can produce free radicals, leading to chain reactions that may damage cells. Antioxidants terminate these chain reactions. Transition metal complexes have been shown to possess encouraging antioxidant activities [23]. Co(II), Ni(II), Cu(II) and Mn(II) complexes of 6-bromo-3-(3-(4-chlorophenyl)acryloyl)-2H-chromen-2-one have been recently found to be effective antioxidants [24]. Generally, antioxidant activity of complexes are determined in- vitro by the hydroxyl radical scavenging, DPPH, NO and reducing power methods [25]. The chemical principles of methods based on biological oxidants comprise superoxide radicals scavenging (O2•-); hydroxyl radical scavenging (HO.); hydrogen peroxide scavenging (H2O2); peroxyl radical scavenging (ROO.) and nitric oxide scavenging (NO.) [26]. Among the non-biological testing scavenging of 2, 2-diphenyl-1-picrylhydrazyl radical (DPPH« assay) and scavenging of 2, 2-azinobis-(3-ethylbenzothiazoline- 6-sulphonate) radical cation (ABTS assay) are mostly experimented. Furthermore, thiobarbituric acid reactive substances (TBARS) and protein carbonyl assays have also been the subject of great attention in this context [27,28]. The novel electrochemical approach to antioxidant activity assay based on the reaction with stable radical 2,2'-diphenyl-1-picrylhydrazyl (DPPH) monitored by the rotating disk electrode (RDE) method has been described advantageous in comparison with usual spectrophotometrical assay since it can be applied to colored compounds and in a wide range of concentrations [29].   

Dementia Relevant Metallic Systems

Alzheimer's disease currently affects over 5.4 million Americans with $236 billion spent annually on the direct costs of patient care [30]. Studies on antioxidant drugs would surely open successful doors to treat AD patients. Seeking for potential antioxidants, chemical behavior of Quercetin as antioxidant and metal chelator has become the subject of intense experimental research [31]. Under comparative antioxidant studies of Co(II), Ni(II), Cu(II) and Mn(II) complexes of 6-bromo-3-(3- (4-chlorophenyl)acryloyl)-2H- chromen-2-one Ni(II) complex shows superior antioxidant activity than other complexes [32]. Commonly it is has been observed that metal complexes may serve as better free radical scavengers [33-35] as compared to the respective free ligands. In some cases antioxidant complexes have rendered a well pronounced larvicidal activity [36]. Hence, synthetic chemistry is playing revolutionary role in human beings by synthesizing novel compounds by different techniques [37]. The target of scientific community has been thus to prepare bioactive compounds relevant to anticancer, antioxidant and enzyme inhibition studies at both the in-vitro as well as in-vivo fronts.   

Biomarkers

Biochemical pathways are famously complex and interconnected, so it’s no surprise that depictions of them have to be simplified (Figure 3). Increasingly, molecular and cell biologists have been coming to terms with the fact that it is hard to decide a label for some protein as a green fluorescent protein (GFP) and expect it to carry on as before. Putting a star next to its name on the whiteboard, or renaming it ‘Target-GFP’, doesn't capture what’s really going on. It is very, very hard to observe living systems at the molecular level without perturbing the very things trying to see, but a great deal of effort is now going into trying to minimize these effects [38]. Under the light shed for evaluation of antidiabetic and antioxidant research, besides developing biomarkers treatment strategies have also been the subject of huge interest. The current status of the aimed field in terms of literature survey is discussed below: (Figure 3).   

Diabetes and Bio-Conjugation

With the aim to continue the enthusiastic search of metallopharmaceutical drugs against diabetes [39,40], thiazolidinediones (TZD) have been reported to be effective anti-diabetic agents that improve insulin sensitivity through the activation of the nuclear receptor and adipocyte-specific transcription factor, peroxisome proliferator-activated receptor gamma (PPAR-γ) [41]. Recently it has been found that Selective PPARγ modulators (sPPARγM) retain insulin sensitizing activity but with minimal side effects compared to traditional TZDs agents [42]. A combination of virtual docking, Surface plasmon resonance (SPR)-based binding, luciferase reporter and adipogenesis assays have been suggested to enlighten the interaction mode, affinity and agonistic activity of L312 to PPARγ in-vitro, respectively [43]. The pharmaceutical isoforms having anti-diabetic effect act by improving the biochemical parameters, this effect is probably due to the high content of polyphenolic compounds found in the formulations [44].

In due course of finding a successful antihyperglycemic candidate, metallic compounds like Vanadium complexes have been well demonstrated in streptozotocin-induced (STZ) diabetic rats and was found that that the vanadate and vanadyl forms of vanadium possessed a number of insulin-like effects in various cells [45]. In the current times basic aspect of diabetes including insulin molecular characterization, chemical basis and its secretion, hypoglycemic drugs and their mode of action associated with diabetes are among the main quests being searched [46]. In an approach of comparative antidiabetic studies of isoforms of BMOV having different metallic centres, it has been found that none so far has surpassed bis (maltolato) oxovanadium (IV) (BMOV) for glucose- and lipid-lowering in an orally available formulation [47]. It is hence clear that ligand and metal selection should be meticulously done to formulate efficient antidiabetic compound.

The bioconjugate chemistry of antihyperglycemic metallic complexes have presented worth some results. The conspicuous application of chromium (III)-amino acid complex against nicotinamide-streptozotocin induced diabetic Wistar rats showed that supplementation of Cr(III)-complex in 8 weeks decreased the blood glucose level in range 46.446-79.593% [48]. Similarly, vanadyl (IV) adenine complex has been introduced as a new drug model for the diabetic complications [49]. Therefore it is expected to be worthy if derivatives of biogenic ligands are formed to design a ligand of favourable properties. For instance, zinc metal-organic framework (MOF) synthesized under mild hydrothermal routes using 5-aminotetrazole and methyl-2- amino-4-isonicotinate anionic ligands has been reported to possess a well pronounced in-vivo antidiabetic activity and low in-vitro cell toxicity [50]. With the same effort,

N,N-Dimethylbiguanide hydrochloride complexes of Neodymium introduced as oral glucose-lowering agent to treat non-insulin dependent diabetes mellitus and to act as antioxidant has shown prominent effect of functional group position in the respective ligands [51].

The medical properties of naturally occurring compounds such as chromones, flavonoids and coumarins are expected to enhance when complex with metal ions suggest the importance of bioconjugate chemical drug research. These complexes can be successfully used in the satisfactory treatment of diseases such as diabetes mellitus [52]. In recent years regulation of the enzymatic activity of human aldose reductase (HAR) has been the main focus of investigation, due to its potential therapeutic application in Diabetes mellitus (DM). Docking behaviour of human aldose reductase (HAR) with different ligands namely such as embelin (Figure 4), copper-embelin complex, zinc- embelin complex, vilangin and quercetin evaluated along with their putative binding sites using Discovery Studio Version 3.1 has shown that that vilangin has maximum interaction energy (-48.94kcal/mol) and metformin with the least interaction energy (19.52kcal/mol) as compared to the other investigated ligands [53]. Therefore, it is strongly suggested that such type of study outcomes might provide new insight in understanding these seven ligands, as potential candidates for human aldose reductase (HAR) inhibitory activity & for the prevention of Diabetes mellitus (DM) associate disorders.

Based on combined in-vitro and in-vitro antioxident evaluation of resveratrol (Figure 5) and molecular modeling studies, it has been indicated that ligand-target interactions/ biological activities are largely dependent on enantiomerism of a target compound [54].   

Antioxidant Activity and Bioconjugation

Antioxidant studies are carried out at the cost of various standard methods [55]. Metal dyshomeostasis is known to be linked with numerous diseases such as Alzheimer's and Parkinson’s diseases, cancer, etc. Recent studies have indicated that some of the metallic compounds of certain ligands may be active while some render inactivity when antioxidant activity test was carried out using picryhydrazyl (DPPH) [56]. On one hand polyphenols have been suggested as efficient antioxidant and anti inflammatory candidates [57] and on the other hand their metallic compounds are expected to exhibit enhanced antioxidant activity due to flexible oxidation state of a metallic centre [58]. Nickel complex of the non-steroidal antiinflammatory drug diflunisal (Hdifl) resulted in the additive antioxidant effect of the respective ligand [59].

The antioxidant activity of the ligand, bis(N-(3-methoxy- salicylidene)-4-amino -phenyl)ether (H2L) and its metal complexes Mn(III) and Cu(II) complexes determined by DPPH, superoxide, hydroxyl and ABTS radical scavenging methods in- vitro, suggest that the Cu(II) complex exhibits greater antioxidant activity against DPPH, superoxide, hydroxyl and ABTS radicals than those of the ligand and the Mn(III) complex [60]. The biotin- 8-hydroxyquinoline conjugates and their metal complexes with manganese(II), cobalt(II), nickel(II), copper(II) and zinc(II) have also been well studied for the possible application in oxidative stress [61]. Similar fashion has been observed with the metallic compounds of

p-coumaric acid [62], 2-(3-amino-4, 6-dimethyl-1Hpyrazolo[ 3,4-b]pyridin-1-yl)aceto-hydrazide [63], chromone Schiff base (Figure 6) [64], etc.

Another important aspect of the antioxidant studies is the strength of a complex not to undergo ROS generation to render a mechanistic action without harming a normal mammalian cell e.g., Ag complex of 1, 10-phenanthroline [65] has shown an interesting behaviour in this context.   

Sugar and Urea Derivative Based Complexes

Urea derivatives bonding through the nitrogen, sulfur and oxygen atoms to the central metal ion form an important class of biologically active ligands. They have been receiving considerable attention due to their pharmacological properties, anti tubercular activity, antiviral potentiality, activity against protozoa small pox and certain kinds of tumour [66]. The chelating characters of thiosemicarbazone have been studied very widely with different metal ions, their complexes with transition and non transition elements were reported.

The ability of sugars to sequester metals is of current interest in the possible development of metal chelates for clinical use and as models for biologically important compounds. Amino sugars form Schiff base with salicylaldehyde and other aromatic aldehydes and only few reports of transition metal complexes of these ligands have been found. Metal chelation could be a rational therapeutic approach for interdicting Alzheimer's disease (AD) pathogenesis. Amyloid plaques that are clusters of proteins and metal ions accumulated between neurons (nerve cells) in Alzheimer's patients’ brains. Enhancing the targeting and efficacy of metal-ion chelating agents through sugar appended ligand is a recent strategy in the development of the next generation of metal chelators.   

Conclusion

From the overall survey it has been established that biomolecules impart great effects in metallic systems to develop molecules of interest. Metallopharmaceuticals are engaged in designing heme-oxygenase and nitric oxide synthase models to bring forth highly demanded gasotransmitter efficiency applicable at various bio-essential routes. Under these circumstances scientific community should fabricate bioconjugated systems to form compounds of human beneficial and multi-purposeful.

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[ptmasterguide]

Gemtuzumab Ozogamicin (Mechanism of Action)

Gemtuzumab Ozogamicin (Mechanism of Action)

In this article, we will discuss Gemtuzumab Ozogamicin (Mechanism of Action). So, let’s get started. Mechanism of ActionGemtuzumab ozogamicin is a CD33-directed antibody-drug conjugate (ADC). The antibody portion (hP67.6) recognizes human CD33 antigen. The small molecule, N-acetyl gamma calicheamicin, is a cytotoxic agent that is covalently attached to the antibody via a linker. Nonclinical data…

[kodavistaa]

Hopping onto this.

relationship status: single

favorite color: blue

three favorite foods: mashed potatoes, pumpkin pie, green onion pancakes

song stuck in my head: We Are All We Need by Joywave

last thing i googled: gemtuzumab ozogamicin (for work)

time: 12:42pm

dream trip: New Zealand!

something i really want rn: to go back to yesterday’s Joywave show

Tagging anyone who wants to do this!

thanks for tagging me @turtlelightwood 🌷💜 RULES: tag 10 people you would like to get to know better

Relationship Status: in an unstable relationship with myself, some other time mentally and platonically dating luke shaw :)

Favourite Colour(s): navy, brown, pink, turquoise, well any shades of blue i think

Three favourite foods: only 3?? omg this is so hard. okay! most of korean and japanese cuisine, french fries, and dim sum. also, special shoutout: frozen yoghurt

Song stuck in my head: たぶん by YOASOBI

Last thing I googled: cities skylines reddit

Time: 3:59 pm

Dream Trip: new zealand (hobbiton, mainly lol), south korea, japan, norway. also some islands in indonesia.

Something I really want right now: finish my uni project and read novels without any distractions

tagging: @colorsofmyseason, @jacksannie, @preachingdoll, @fanficburner, @vividic, @protect-daniel-james, @millythegoat, @thingsdivine, @happyisholy, @cyncity2000

[pharmaphorumuk]

Antibody-drug conjugates on the march

One of AstraZeneca’s most decisive moves last year came in March, when it signed a multi-billion dollar deal with Japan’s Daiichi Sankyo, focused on just one breast cancer drug. But with the drug, Enhertu, now approved in the US, doctors could have a powerful new medicine in their arsenal against breast cancer. Richard Staines spoke with Gilles Gallant, Daiichi’s oncology R&D team leader about the future plans for the drug, and the antibody-drug conjugate technology behind it.

When AZ was penning its deal with Daiichi, CEO Pascal Soriot was so convinced in the potential of the drug, codenamed DS-8201 at the time, that he asked investors to fund the deal with a share offer worth around $3.5 billion.

DS-8201 is a buffed version of Roche’s breast cancer drug Herceptin (trastuzumab), which adds the lethal cancer-killing payload deruxtecan to the HER2-targeting antibody’s structure using a special “linker�� molecule.

This only breaks once the antibody binds to HER2 found on cancer cells, administering the dose of deruxtecan inside the cell, which dies as a result.

Roche has already used this kind of antibody-drug conjugate (ADC) technology to produce its Kadcyla (trastuzumab emtansine), but with this new ADC, branded as Enhertu, AZ and Daiichi are targeting patients who have failed to respond to two HER2-targeting therapies.

This would set it up for use after Herceptin or Roche’s other breast cancer drug Perjeta, and after treatment with Kadcyla.

“We have passed the era of immunotherapy – cell therapy is here. ultimately we will need to find ways to combine all of these to prolong progression-free survivaL”

At the moment US approval is only conditionally approved based on response rates seen in a phase 2 trial, with survival data coming from the larger ongoing DESTINY-Breast 02 trial.

But the 60.3% response rate seen in the phase 2 Destiny-Breast 01 trial is impressive in patients with such advanced disease.

The companies think it could also outperform Kadcyla and is being tested in the DESTINY-Breast03 trial, a head-to-head comparison with Roche’s rival ADC.

But Daiichi’s oncology team leader Gilles Gallant said there is much more to come from Enhertu, which could be used in earlier stages of the disease, and in other cancers expressing HER2.

The drug could have a wider remit than Herceptin thanks to the power of the deruxtecan component, which is enough to produce a cancer-killing effect even in tumours that barely express HER2.

While Herceptin on its own may bind to ‘HER2 low’ tumours with little effect, Enhertu’s payload is strong enough to kill cancer cells even at very low doses.

“It can bind to HER2 low tumour cells and deliver the payload, and has a different mechanism of action,” he explained.

“When we talk about having HER2-low it does not mean that they have not got the HER2 receptor. It just means that they have less, much less. Other drugs in the past that were HER2-directed tried to be active in those particular patients.”

A place in the world for ADCs

Going forward, Gallant said that that ADC technology is going to be one of several innovations that will help improve the prognosis in a range of cancers.

He sees it as a separate area of research in oncology, after the recent success in areas such as immunotherapy.

ADC drugs like Enhertu could be used as either a monotherapy, or in combination with other forms of cancer therapies.

The first approved ADC was Pfizer’s Mylotarg (gemtuzumab ozagimicin), which the FDA backed as long ago as 2000 in AML.

Mylotarg was initially a commercial flop and was withdrawn in 2010 because of safety issues in a trial that was supposed to confirm its benefit-risk profile after a tentative approval based on early data.

But it was reapproved in 2017 after a campaign by oncologists who wanted to see another treatment option for CD-33 positive patients.

Seattle Genetics and Astellas’ Adcetris (brentuximab vedotin) was the second ADC to be approved for certain forms of lymphoma, followed by Roche’s Herceptin-based ADC, Kadcyla.

The FDA late last year okayed another Seattle/Astellas ADC, Padcev (enfortumab vedotin) in bladder cancer, which was a star of last year’s American Society of Clinical Oncology (ASCO) conference.

Gallant said: “To me it’s a different arm, a different part of what we have available to go after cancer. Of course you will have to combine it. Some of the successes we have had in the past were with combinations.

“You have to consider we have passed the era of immunotherapy – cell therapy is here with CAR-T treatments. They ALL work with different mechanisms of action and I think ultimately we will need to find ways to combine all of these to either prolong progression-free survival or better overall survival.

“This is the first that has been approved but we have six others with similar technology, three of those are already in the clinic and three more are coming to the clinic in the next year or two.”

Pipeline and Seattle issues

A glance at Daiichi’s pipeline underlines the importance of ADCs to the company. Aside from breast cancer Enhertu is also in the clinic in gastric, colorectal, breast and lung cancer uses.

Three other ADCs are in early stage trials for HER3 expressing breast cancer EGFR-mutated non-small cell lung cancer (NSCLC), NSCLC, and solid tumours.

It’s early days for these and there are many hurdles to overcome, particularly as safety issues have cropped up with ADCs in the past.

Enhertu was approved with a warning about risk of interstitial lung disease, and the safety issues with Mylotarg are well documented.

There is also another threat to Daiichi in the form of a legal feud with Seattle Genetics, which specialises in ADCs and worked with Daiichi in this area in an R&D tie-up between 2008 and 2015.

Seattle argues that the linker technology used in Enhertu derives from that partnership, something that Daiichi is contesting in court.

Gallant argues that Enhertu uses a completely different linker from that seen in the tie-up with Seattle, which was based around a different antibody targeting DR5.

“The linker in the payload are completely different. It is important to understand that these are significantly different.”

The target, payload and linker all differ from the one seen in according to Gallant, who is says Seattle’s claim is “without merit”.

Legal issues aside, great things are expected of Enhertu, with peak sales predicted to be north of $4 billion annually, with some analysts suggesting a peak of around $7 billion.

After a slow start 20 years ago with Mylotarg, it seems like ADCs could finally be coming of age.

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