Antibody-Based Approaches to Cancer Therapy

Describe features of biologics

Any medicinal product manufactured in, or extracted from, biological sources (as distinct from chemically synthesised pharmaceutical products). E.g. vaccines, recombinant proteins, enzymes etc.

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What are the strategies for the use of mAbs as anti-cancer agents?

Single agents (mono-specific), bispecific antibodies, conjugated cytotoxic agents (ADCs), conjugated to radiopharmaceuticals, conjugated cytokines, conjugated to nanoparticles (liposomes), ADEPT

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Outline the anatomy of antibodies (1)

4 chains, 2 heavy chains joined by disulphide/hinge region, 2 light chains, chains produced separately then joined together in cell. Variable region, constant region. Cell changes sequence of amino acids on antibody, change recognition of antigens

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Outline the anatomy of antibodies (2)

Dimeric, tetrameric, pentameric, used of antibody fragments/bispecific antibodies. Use of hybridoma technology to produce mAbs

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What are the types of antibodies?

Murine mAbs, chimeric antibodies, humanised antibodies, human mAbs

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Describe features of single-agent antibodies (1)

Antibody dependent cell mediated cytotoxicity – antigen interacts with antigen (on tumour cell), T-cell/killer cell have Fc receptors which binds to Fc region of the antibody, T cell kills the tumour cell (ADCC effect)

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Describe features of single-agent antibodies (2)

T cell releases biochemical to kill tumour cell. E.g. Trastuzumab (Herceptin), Cetuximab, Bevacizumab

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Describe features of biosimilars

Help with costs. Antibodies are glycoproteins (sugars attached to antibody), difficult to reproduce exactly the same antibody (sequence of sugars, variation in mwt)

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What are the targets for check point inhibitors?

CTLA-4 and CD28 - use of PD-1 and PD-L1 inhibitors

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What are bispecific mAbs?

Monoclonal antibodies which can bind to different antigens presenting cells, greater selectivity for tumour cell

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Describe features of antibody drug conjugates (1)

Components - antibody, tumour antigen, cytotoxic payload, linker and conjugation technologies. Antibody kills tumour cell, doesn’t go into healthy tissue. ADC structure (antibody-linker-drug), increases therapeutic window compared to chemo/radiation

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Describe features of antibody drug conjugates (2)

MOA - ADC delivers payload to interior of cancer cell leading to cell death by apoptosis

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What is the bystander effect?

If some release occurs externally to the cancer cell, then the drug is free to diffuse into neighbouring cells, a phenomenon known as the bystander effect. Payload may also diffuse (or be pumped via pGp) out of a cell and provide a bystander effect.

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What are the types of payload?

Microtubule-interactive, DNA-interactive, protein-based toxins

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Give examples of payloads currently at the discovery or development stages

RNA polymerase II and III inhibitors, tubulin inhibitors, spliceostatins, protein toxins, cytokines, chemokines, ATPase inhibitors

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What is the issues with the conjugation of payloads?

High hydrophobicity, toxicity

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What are the most desirable properties of payloads for ADCs? (1)

High cytotoxic potency. Good physicochemical properties. Effective cell kill mechanism with low toxicity in healthy cells. Low resistance. Poor substrate for cell efflux. Choice of linker attachment points. Stable linker-payload

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What are the most desirable properties of payloads for ADCs? (2)

Free payload has limited cellular permeability. Chemically tractable. Cost effective synthesis of GMP supply

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Describe features of tubulin inhibitors (1)

Tubulin forms spindle structures (cell division – formation of daughter cells), gives rigidity to cell (structural purposes). Drugs interact with tubulin. Two MOA for tubulin inhibitors

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Describe features of tubulin inhibitors (2)

E.g. colchicine, vinca alkaloids, halichondrins, taxol alkaloids, taxol analogues, epothilones, auristatins (ADC payloads), brentuximab vedotin, maystansins (ADC payload), trastuzumab emtansine

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Give examples of early DNA interactive cytotoxic agents

DNA intercalating agents (doxrubicin), topoisomerase inhibitors (camptothecin, topo I inhibitor)

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Give examples of currently used DNA interactive ADC payloads

DNA cross linking agents e.g. PBD dimers. DNA alkylating agents e.g. duocarymycins. DNA cleaving agents e.g. calicheamicin, gemtuzumab ozogamicin, trastuzumab duocarmazine

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State features of novel linker strategies (1)

SynAffix ADC Linker Technology. Hydraspace – two different payloads (overcome resistance by using a combination of payloads, tumour unlikely to develop resistance to two different types of payloads). Tagworks (chemically triggered release)

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State features of novel linker strategies (2)

Aspyrian light triggered release technology. Alternative non-antibody targeting vehicles. Disease-Related Ligands - Folic Acid (Endocyte Inc). Bicycles (Bicycle Therapeutics)

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Describe features of antibody-radionuclide conjugates (RIT)

Attach a radionuclide as the toxic “payload”. To limit radiation exposure, murine antibodies are used, as their high immunogenicity promotes rapid clearance from the body. Ibritumomab Tiuxetan

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Give other examples of novel techniques

Antibody-cytokine conjugates (immunocytokines). Antibody-Nanoparticle Conjugates (e.g., Immunoliposomes). ADEPT (Antibody-Directed Enzyme Prodrug Therapy

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Antibody-Based Approaches to Cancer Therapy

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