Basics of Biologics 3900-BT1-3

Lecture 1 — Introduction: history and types of biologics. From serum therapy and extractive insulin to recombinant proteins, monoclonals, nucleic acids and living cells. The modality landscape and the classification that matters: what the active substance is, how it is made, how it is regulated, and how long its effect lasts. Small molecule versus biologic as a set of trade-offs — target space, specificity, oral availability, manufacturing cost, immunogenicity, cost of goods. Biosimilars versus generics, and why identity cannot be established for a biologic by chemical analysis alone.

Lecture 2 — Small RNA-based biologics: siRNA, miRNA, ASO. Two distinct mechanisms: RNase H-dependent cleavage by gapmer antisense oligonucleotides, and RISC-mediated silencing by siRNA. Steric-block antisense as a third mode, with splice modulation as its clinical showcase. Chemical modification as the enabling technology — phosphorothioate backbones, 2′-O-methyl and 2′-MOE sugars, locked nucleic acids, and the toxicity and protein-binding consequences each carries. Why microRNA therapeutics have proved harder than either: pleiotropy, the difficulty of a therapeutic index for a multi-target agent, and the lessons of discontinued programmes. Off-target hybridisation, seed-based effects, and innate immune activation as the three characteristic liabilities.

Lecture 3 — Delivering RNA-based biologics. The delivery problem stated quantitatively: what fraction of an administered dose reaches the cytoplasm of a target cell, and where the rest goes. Lipid nanoparticles — ionisable lipid, helper phospholipid, cholesterol, PEG-lipid — and the apolipoprotein-mediated route that makes hepatocytes the default destination. Endosomal escape as the rate-limiting step, and why single-digit-percent escape is still considered good. Receptor-targeted conjugates and the GalNAc–asialoglycoprotein receptor system that turned hepatic siRNA into a subcutaneous, twice-yearly medicine. Extrahepatic targeting: charge, ligand, and organ-selective formulation strategies. PEG immunogenicity, complement activation, dosing intervals, and the manufacturing constraints of nanoparticle products.

Lecture 4 — mRNA-based therapies: vaccines and others. Anatomy of a therapeutic mRNA: cap structure and co-transcriptional capping, untranslated regions, codon usage, poly(A) tail length, and nucleoside modification. Why substituting modified uridines suppresses innate sensing, and how that observation converted mRNA from an immunostimulant into a drug. Self-amplifying and circular RNA as alternative architectures with different dose and duration profiles. Applications beyond prophylactic vaccination: cancer neoantigen vaccines, protein replacement, secreted antibodies, and transient in vivo cell engineering. Cold chain, stability, and the process-analytics problem of a product defined largely by its impurities.

Lecture 5 — Gene therapy and CRISPR/Cas9-based technologies. In vivo versus ex vivo strategies. AAV as a delivery platform: serotype tropism, capsid engineering, episomal persistence and the consequent loss of effect in dividing tissue, pre-existing neutralising antibodies, dose-dependent hepatotoxicity and complement activation. Lentiviral vectors for ex vivo modification, integration site distribution, and the insertional mutagenesis history that shaped the field's safety framework. Genome editing: nuclease-induced double-strand breaks and their repair outcomes, base editing and prime editing as alternatives that avoid the break, and delivery as the limiting factor in each. Off-target assessment, mosaicism, germline boundaries, and the ethical and regulatory frame.

Lecture 6 — Protein-based biologics: therapeutic antibodies. Immunoglobulin architecture mapped onto function: antigen binding, effector recruitment, FcRn-mediated half-life. Discovery routes — hybridoma, display, transgenic animals, and structure-guided design — and the humanisation and affinity-maturation steps that follow. Fc engineering to dial effector function up or down, glycosylation as a critical quality attribute, and half-life extension. Formats beyond IgG: fragments, bispecific and multispecific antibodies, antibody–drug conjugates and their linker–payload logic. Developability as a discipline: aggregation, viscosity, chemical liabilities in the CDRs, and immunogenicity prediction.

Lecture 7 — Cell-based therapies: CAR-T and T-cell engagers. Chimeric antigen receptor architecture — binder, hinge, transmembrane, costimulatory and signalling domains — and how each generation changed persistence and potency. Manufacturing an autologous product: apheresis, transduction, expansion, release testing, vein-to-vein time. Lymphodepletion and its rationale. Cytokine release syndrome and neurotoxicity as on-mechanism toxicities with defined management. Bispecific T-cell engagers as an off-the-shelf alternative with different pharmacokinetics and different toxicity kinetics. Why solid tumours remain resistant: trafficking, the suppressive microenvironment, antigen heterogeneity and escape. Allogeneic and in vivo CAR generation as the field's current direction.

Lecture 8 — Cell-based therapies: neurodegeneration. What cell therapy can and cannot address in a degenerating nervous system: replacement of a defined lost cell population versus modification of a diffuse degenerative process. Parkinson's disease as the tractable case — fetal tissue grafting and what it demonstrated, the move to pluripotent stem cell-derived dopaminergic progenitors, graft survival, innervation, and the immunosuppression question. Autologous versus allogeneic sourcing and the tumorigenicity assessment that any pluripotent-derived product requires. Delivery to the central nervous system: stereotactic administration, the blood–brain barrier, and the intrathecal and capsid-engineered routes used by other modalities. Trial design where the endpoint is slow and the placebo response substantial.

Lecture 9 — Cell-based therapies: the microbiome. The live biotherapeutic product as a regulated drug class distinct from both food supplements and conventional biologics. Faecal microbiota transplantation as the proof of principle in recurrent Clostridioides difficile infection, and the standardised products that followed it. Defined bacterial consortia and the rationale for moving from an undefined donor material to a characterised, manufacturable one. Engineered live biotherapeutics: bacteria as in situ production platforms, with containment and biosafety as design requirements. Colonisation resistance, engraftment measurement, donor screening, and the reasons efficacy in other indications has been harder to demonstrate than the mechanistic rationale suggested.

Lecture 10 — Protein-based biologics: glucose homeostasis. Insulin as the field's founding biologic and its continuing engineering: analogues designed for rapid absorption or flat multi-day action through amino acid substitution, isoelectric shifting and fatty-acid acylation. Incretin biology and its therapeutic exploitation — GLP-1 receptor agonists, the half-life problem of a native peptide with a two-minute existence, and the acylation and fusion strategies that solved it. Dual and triple receptor agonists, and the shift from glycaemic control to weight as the primary outcome. Oral peptide delivery and permeation enhancement. Glucose-responsive and closed-loop concepts. This unit is also the course's clearest illustration of peptide engineering as a discipline in its own right.

Lecture 11 — Drugging the undruggable: PROTAC and targeted protein degradation. The limits of occupancy-driven pharmacology and the case for event-driven, catalytic mechanisms. Ternary complex formation between target, degrader and E3 ligase; cooperativity and the hook effect; why a degrader's potency is not a binding constant. The ligase toolbox in practice and the small number of ligases actually exploited. Molecular glues, including the retrospective explanation of thalidomide's activity, and the discovery problem they pose. Degradation of extracellular and membrane proteins, and autophagy-directed approaches for aggregates and organelles. Medicinal chemistry beyond conventional oral-drug property space, resistance through ligase loss, and where degraders stand clinically.

Lecture 12 — Biologics in clinical use: from bench to bed. What separates a working molecule from an approved medicine. Chemistry, manufacturing and controls for products defined by their process; potency assays and comparability after a process change. Immunogenicity assessment and anti-drug antibody consequences. Regulatory routes for biologics, advanced therapy products and biosimilars, and what conditional and accelerated approvals do and do not assert. Pricing, reimbursement and access for one-time therapies with lifetime effects. Ultra-rare and n-of-1 interventions and the framework built to accommodate them. Post-marketing surveillance, long-term follow-up obligations for gene and cell products, and the failure modes that only appear at scale.