Prot eins Immune Checkpoint

CONTENTS Page 3 Immune System Page 7 Cancer and Immune Response Page 9 Immuno-Oncology Page 12 Immune Checkpoint Proteins Page 22 Immune Checkpoint Immune Checkpoint Therapy

01 Immune System What is immune system How does the immune system work

Immune System The immune system is made up of a network of cells, tissues, and organs that work together to protect the body from harmful things like germs, viruses, and diseases like cancer. To function properly, an immune system must detect a wide variety of agents, known as pathogens, from viruses to parasitic worms, and distinguish them from the organism's own healthy tissue. After first finding a foreign substance, the immune system takes action to destroying foreign substance and abnormal cells, including cancer cells.

Immune System Humoral Immunity Cytoimmunity Cell-mediated, in which T cells identify and destroy abnormal cells, including those that are cancerous. Humoral, also called antibody-mediated, in which B cells make antibodies that identify and destroy foreign substances.

Immune System e.g. The use of immunosuppressive medication Immunodeficiency immune system is less active than normal, resulting in recurring and life- threatening infections. Disorders Both an overactive and an underactive immune system can be harmful. Autoimmune Diseases Inflammatory Diseases Cancer Autoimmunity Hyperactive immune system attacking normal tissues.

02 Cancer and Immune Response Normal Adapt & Mutate

Cancer and Immune Response Normally, our immune system is, like it’s supposed to, able to destroy cancer cells in our body, however, sometimes cancer cells can adapt and mutate, effectively hiding from our immune system, allowing cancerous cells to grow and spread. This is why tumors can develop and become a threat to our health.

03 Immuno-Oncology Fight Promote Immune System Cancer

Immuno-Oncology Immune-oncology Advantages Targeted, unharmed to other cells The fewer limitation on the stages Current Treatments Surgery Chemotherapy Methods Radiation

Immuno-Oncology 01 Immune Cell Therapy (CAR-T) 02 Cytokines 03 Monoclonal Antibodies 04 Cancer Vaccines 05 Checkpoint Inhibitors

04 Immune Checkpoint Proteins A CLAT-4 B PD-1/PD-L1 C Other Immune Checkpoint Proteins

Immune Checkpoint Proteins What are Immune Check Points Immune checkpoints are regulators of immune activation. They play a key role in maintaining immune homeostasis and preventing autoimmunity. B7 PD-L1 B7 CD28 CTLA-4 PD-1

CTLA-4 Cytotoxic T Lymphocyte antigen 4 (CTLA-4) (CD152) and CD28 are homologous receptors expressed by both CD4 + and CD8 + T cells, which mediate opposing functions in T cell activation. Both receptors share a pair of ligands expressed on the surface of antigen presenting cells (APCs).

CTLA-4 CD28 B7-1/2 T Cell Activation B7-1/2 CLAT-4 CD28 >>> Higher Affinity T Cell Activation

CTLA-4 B7-1/2 CLAT-4 CD28 >>> Higher Affinity 20 Times Trans-endocytosis

CTLA-4 CD28 B7-1/2 Cytotoxicity CTLA-1 Blockade ADCC

PD-1/PD-L1 PD-1 predominantly regulates effector T cell activity within tissues and tumors 0102 CTLA-4 regulates T cell activation in lymphoid organs PD-1 is primarily expressed on mature T cells in peripheral tissues and the tumor microenvironment 03 CTLA-4 mainly affects naïve T cells 04

PD-1/PD-L1

Other Immune Checkpoint Proteins Immune Checkpoint ProteinSynonymCellular ExpressionLigand PD-1 (immune suppressive checkpoint) CD279 Activated T cells in peripheral tissue, B cells, professional APCs, NK cells PD-L1 (CD274, B7-H1) and PD-L2(CD273,B7-DC) LAG-3 (immune suppressive checkpoint) CD223Activated T cells, NK cellsMHC class II TIM-3 (immune suppressive checkpoint) HAVcr2 Activated T cells and tissues such as liver, small intestine, thymus, spleen, lung muscle, brain tissue Mainly galectin-9, as well as phosphatidylserine and HMGB1 CTLA-4 (immune suppressive checkpoint) CD152Mostly naive CD4 + and CD8 + T cells, Tregs CD80 (B7-1) or CD86 (B7-2) KIRs (immune suppressive checkpoint) CD158 Mainly NK cells but also APCs and tumor associated CTLS MHC class I molecules (HLAs) GITR (immune activating checkpoint) CD357Tregs, activated CD4 + and CD8 + T cellsGITRL 4-1BB (immune activating checkpoint) CD137 Activated CD4 + and CD8 + T cells, Tregs, activated NK cells, DCs, neutrophils 4-1BB-L

05 Immune Checkpoint Therapy Advantage of Immunotherapy Attention to Immunotherapy

Some Selected Immunotherapeutic Agents in Clinical Trials TargetNameAntibody ClassDiseasesStatusCompany CTLA-4 Lpilimumab (Yervoy) IgG1k Melanoma Non-small/small cell lung cancer FDA Approved Bristol-Myers Squibb tremelimumabIgG2melanoma Completed Phase III Pfizer, now Medimmune PD-1 Nivolumab/BMS /MDX1106 IgG4melanomaPhase III Bristol-Myers Squibb Pidilizumab/ CT-011 IgG1 non-Hodgkin’s lymphoma, chronic lymphocytic leukemia, Hodgkin’s lymphoma, multiple myeloma, acute myeloid leukemia Phase I/IICureTech Pembrolizumab/MK-3475IgG4HNSCCPhase IMerck PD-L1 BMS /MDX-1105IgG4various cancersPhase I/II Bristol-Myers Squibb MEDI4736IgG1k Select Advanced Malignancies Phase I MedImmune/ AstraZeneca

Immune Checkpoint Therapy Digestive Tract Symptoms Loss of Appetite Flu-like Symptoms Fatigue

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