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#targeted therapy

12 public questions tagged with this topic.

Immunological Applications

Ado-trastuzumab emtansine is used against:

HER2 positive metastatic breast cancers progressing after trastuzumab plus chemotherapy develop resistance mechanisms including truncated p95HER2 lacking extracellular binding epitope, upregulation of MUC4 masking epitope, activation of downstream PIK3CA H1047R mutation, and alternative receptor tyrosine kinase signaling AXL. Ado-trastuzumab emtansine also called T-DM1 extends HER2 targeting beyond signaling inhibition delivering cytotoxic maytansine chemically. Trastuzumab backbone retains anti-signaling activity via inhibition of HER2 heterodimerization and metalloprotease cleavage, suppress

Ref: Verma et al NEJM 2012 367:1783 EMILIA T-DM1 HER2 DM1 non-cleavable; FDA ado-trastuzumab emtansine label.

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Immunological Applications

Brentuximab vedotin targets:

CD30 antigen also designated TNFRSF8, 120 kDa type I transmembrane glycoprotein member tumor necrosis factor receptor superfamily characterized by cysteine rich domains extracellularly and TRAF binding motifs intracellularly activating NF-kB, transiently expressed on activated B and T lymphocytes but constitutively highly expressed on Reed-Sternberg giant cells of classical Hodgkin lymphoma and anaplastic large cell lymphoma ALCL, and small subset cutaneous T cell lymphomas, making near tumor specific target with minimal normal tissue expression limited to activated immune cells conferring fav

Ref: Younes et al NEJM 2010 363:1812 Brentuximab vedotin CD30 MMAE valine citrulline; Seattle Genetics Adcetris approval.

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Immunological Applications

Antibody–drug conjugates (ADCs) combine:

Antibody-drug conjugates integrate precision of biologics with potency of small molecules to overcome poor therapeutic window of conventional chemotherapy that diffuses into all tissues causing systemic toxicity. Monoclonal antibody component provides tumor-selective homing through high affinity binding Kd 10^-9 to 10^-11 M to antigens preferentially expressed on malignant cells ten to hundred fold over normal tissues, such as HER2, CD30, CD22, and internalization via receptor mediated endocytosis clathrin dependent trafficking to early endosome then late endosome fusing with lysosome pH 4.5 c

Ref: Beck et al Nat Rev Drug Discov 2017 16:315 ADC linker payload MMAE DM1; Trail Cancer Immunol Res auristatin maytansine.

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Immunological Applications

Immunotoxins kill target cells mainly by:

Mechanism by which protein toxins arrest protein synthesis culminates in rapid programmed cell death via mitochondrial pathway capable of killing quiescent cells. Diphtheria toxin fragment A catalyzes ADP-ribosylation of unusual post-translationally modified histidine diphthamide at position 699 of eukaryotic elongation factor 2 present exclusively on domain IV, using oxidized NAD+ as ADP-ribose donor releasing nicotinamide. Modified elongation factor cannot mediate translocation step of peptidyl-tRNA from A site to P site on 60S ribosomal subunit, halting elongation after single round. Ricin

Ref: Collier Annu Rev Biochem 1975 diphtheria ADP-ribosyl EF2; Olsnes Pharmac Ther ribosome N-glycosidase ricin apoptosis.

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Immunological Applications

Immunotoxins are composed of:

Immunotoxins constructed to overcome lack of selectivity of conventional chemotherapy achieve tumor specific delivery of ultrapotent protein toxins that cannot enter mammalian cells unaided. Design consists of targeting moiety typically single-chain variable fragment scFv or disulfide stabilized Fab derived from murine or humanized antibody recognizing tumor antigen CD22 on hairy cell leukemia, CD25 on adult T cell leukemia, mesothelin on mesothelioma, linked via flexible glycine-serine peptide or reducible disulfide bond formed between engineered cysteines to effector toxin devoid of native r

Ref: Pastan et al Nature Rev Cancer 2006 6:559 immunotoxins PE38; Kreitman Clin Cancer Res 2009 fusion toxin de-immunized.

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Immunological Applications

The prodrug in abzyme therapy is:

Abzyme-directed prodrug therapy also known as ADAPT aims to combine tumor-targeting specificity of antibodies with catalytic turnover allowing one antibody molecule to activate many prodrug molecules amplifying effect. Conventional systemic chemotherapy distributes throughout body causing dose limiting myelosuppression, alopecia, mucositis due to toxicity to rapidly dividing normal tissues such as bone marrow and gastrointestinal epithelium. Prodrug strategy masks cytotoxic warhead with cleavable moiety ester, carbamate, glucuronide, or phosphate rendering molecule 100 to 1000 fold less toxic,

Ref: Shabat et al PNAS 1995 ADAPT abzyme prodrug site activation; US Patent 5948647 antibody directed prodrug therapy.

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Immunological Applications

Monoclonal antibodies bind:

Monoclonal antibody originates from unique genetic event where one developing B cell successfully completed VDJ recombination on heavy chain locus chromosome 14 mediated by RAG1/2 recognition of recombination signal sequences, non-homologous end joining with TdT adding N nucleotides creating unique complementarity determining region three loop that dominates antigen contact, plus VJ recombination on light chain locus producing paired variable domains. All progeny via mitosis carry identical nucleotide sequence encoding paratope whose three-dimensional shape, electrostatic surface, and hydropho

Ref: Abbas Cellular Molecular Immunology 10th ed monoclonal single epitope uniform affinity; Roitt Essential Immunology specificity.

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Immunological Applications

Brentuximab vedotin targets:

Brentuximab vedotin Adcetris exemplifies first approved CD30-directed antibody-drug conjugate transforming management Hodgkin lymphoma systemic anaplastic large cell lymphoma peripheral T-cell lymphoma uniformly expressing CD30 TNFRSF8 120 kDa type I transmembrane signaling TRAF1 TRAF2 TRAF5 activating NF-kB MAPK promoting survival malignant clone. Murine chimeric cAC10 IgG1 human constant murine variable binds ECD residues 19-38 affinity 5 nM complex rapidly internalizes 2-4h CD30-mediated clathrin-dependent endocytosis delivering conjugate lysosomal compartment acidic pH proteases degrade an

Ref: FDA Adcetris Brentuximab Vedotin CD30 Target Label Mechanism; NEJM Brentuximab Hodgkin Lymphoma Efficacy 2012 Younes et al; Trail ADC CD30 Mechanism Review.

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Immunological Applications

Antibody–drug conjugates (ADCs) combine:

Antibody-drug conjugates engineered targeted chemotherapy combining precision monoclonal antibody recognition lethal payload potency too toxic systemic administration alone narrow therapeutic index causing severe myelosuppression neuropathy. Monoclonal antibody component typically humanized IgG1 kappa 150 kDa produced CHO cells reduced fucosylation enhancing Fc gamma receptor affinity binds tumor-associated antigen nanomolar affinity CD30 120 kDa TNFRSF8 Hodgkin Reed-Sternberg anaplastic large cell HER2 185 kDa tyrosine kinase amplified breast adenocarcinoma CD33 67 kDa sialic acid-binding Ig-

Ref: FDA Guidance Antibody Drug Conjugates 2020 Principles; Nature Reviews Drug Discovery ADC Technology Evolution 2022; Trail et al Antibody Drug Conjugates Design Development.

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Immunological Applications

Which toxin is commonly used in immunotoxins?

Diphtheria toxin produced Corynebacterium diphtheriae lysogenized temperate corynephage beta carrying tox gene regulated iron-dependent repressor DtxR provides ideal warhead immunotoxin because catalytic mechanism well characterized potency extreme one molecule sufficient kill cell enzymatic turnover inactivating millions ribosomes extensive clinical experience vaccine toxoid. AB architecture A domain catalytic 21 kDa active site Glu148 critical nucleophile performing NAD-dependent ADP-ribosylation EF2 B domain receptor-binding translocation B composed receptor-binding subdomain C-terminal 482

Ref: Pastan Diphtheria Toxin Immunotoxin Clinical Development 2009; FDA Ontak Tagraxofusp DT Fusion Mechanism Label; Collier Diphtheria Toxin Structure Function Catalysis Enzymology.

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Immunological Applications

Immunotoxins kill target cells mainly by:

Protein toxins employed immunotoxin design kill primarily through catalytic inactivation protein synthesis machinery requiring only few molecules cytosol triggering irreversible apoptosis. Diphtheria toxin fragment A 21 kDa ADP-ribosyltransferase modifies diphthamide residue unique post-translationally modified histidine 699 eukaryotic elongation factor 2 synthesized seven enzymes DPH1-7 adding 3-amino-3-carboxypropyl trimethylation diphthine amidation transferring ADP-ribose oxidized NAD imidazole inhibiting translocation peptidyl tRNA A site P site elongation cycle 80S ribosome mediated GTP

Ref: Collier 1967 Diphtheria Toxin ADP-ribosylation EF2 Discovery; Pastan PE38 Protein Synthesis Inhibition Mechanism; Lodish Protein Synthesis eEF2 Function Chapter 7.

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Cell Signaling ELR Pathways - I

Tyrosine kinase inhibitors are used clinically to treat

cancers, is consistent with established principles of cell signaling, receptor pharmacology and cellular regulation. Experimental measurements of binding parameters, genetic loss-of-function studies and pharmacological interventions all converge on the same interpretation. Related options address neighboring concepts but do not satisfy the precise criterion stated in the question.

Ref: NCERT Biology Class 11–12 Alberts et al Molecular Biology of the Cell Lodish et al, Molecular Cell Biology Cooper & Hausman, The Cell Abbas et al., Cellular and Molecular Immunology (for immunology sections)

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