Download BiTE® ANTIBODIES: Designed to Bridge T Cells

AN INVESTIGATIONAL TECHNOLOGY FROM AMGEN
BiTE ANTIBODIES
®
Designed to Bridge T Cells to
Cancer Cells
Cytotoxic T Lymphocytes (CTLs) Are
Highly Specific and Potent Effector Cells
C
ytotoxic T-Lymphocytes (CTLs) have an innate ability to target tumor
cells, and evidence supports a role for immunosurveillance in tumor
targeting. By recognizing and binding to tumor cells, CTLs can lead to
tumor cell lysis. To affect tumor cell lysis, CTLs require cell-to cell contact.1
However, tumor cells have developed various mechanisms that can
prevent an antigen-specific CTL response and evade T cell recognition.2
T reg cell
Suppressive factors within the tumor
microenvironment may inhibit effector
cells that manage to access the tumor
Mature T cell
Tumor cells can evade destruction by
• Modification of tumor microenvironment
by secretion of immunosuppressive
cytokines such as TGF-β2
• Modification of immune cell repertoire
by stimulation of immunosuppressive
response2,3
• Generation of IDO2
Naïve T cell
Dendritic cell
Inhibition of T cell
priming by interleukins
Dendritic cells may not
recognize antigens as targets
for destruction
Tumor cell
cytotoxic T cells
• Loss or mutation of MHC class I on
tumor cells2
• Interference with perforin/
granzyme pathway4,5
• Exploitation of immune-checkpoint proteins
• Increased CTLA-4 expression on
T cells counteracts CD284
• Increased PD-1 expression on T cells4
• Inhibition of kinases involved in
T cell activation5
• Persistent PD-1 expression causing
T cell exhaustive state5
• Increased PD-L1 expression on tumor
cell surface4
Recent Approaches in Oncologic Therapies
T
he aim is to harness and enhance the cytotoxic activity of T cells
against tumor cells*
1. Allogeneic HSCT: Tumor cells are eliminated through chemotherapy
and graft versus tumor effect6–9
2. Adoptive Cell Therapy: Adoptive cell therapy utilizes autologous
antitumor activity of cells such as tumor-infiltrating lymphocytes, to
treat cancer10
3. Immunovirus: Using a modified virus that has the potential to induce tumor
cell lysis through replication within tumor cells and activation of T cells11–14
4. CTLA-4 Checkpoint Inhibitors: Anti-CTLA-4 mAbs augment T cell
activation by blocking inhibitor receptors such as CTLA-4.5,15
*Some of these mechanisms are still under investigation.
5
2
1
3
4
8
7
6
BiTE® antibody
mAb
for TAA
mAb
for CD3
5. PD-1/PD-L1 Checkpoint Inhibitors: Checkpoint inhibitors against PD-1
and its ligand PD-L1 release PD-1 pathway-mediated inhibition of T cell
activation5
6. Autologous Active Cellular Immunotherapy: Activated antigenpresenting cells are reinfused into patients to direct immune cells against
target cancer cells16
7. CAR-T Cells: Modified chimeric antigen receptor (CAR)-T cells redirect
T cell antigen specificity, activation and further enhance T cell function
via costimulation domains in the cytoplasmic tail17,18
8. BiTE®: BiTE® antibody constructs bridge CD3-positive CTLs to cells
expressing specific cell surface antigens, resulting in the release of
proteolytic substances against the target cell(s)19–21
Bispecific T Cell Engager (BiTE®) Antibodies
I
nvestigational Bispecific T cell engager (BiTE®) Antibodies are designed
to bridge cancer cells to CTLs.22 The BiTE® antibody construct utilizes the
binding properties of the variable domains of two monoclonal antibodies.23
One domain is designed to target an antigen on the surface of a cancer
cell whereas the other is designed to engage CD3 on the surface of a
T cell.23 With these two different domains, BiTE® antibodies aim to engage
the endogenous cytotoxic potential of CTLs, bypassing MHC/antigendependent activation of T cells.21,24,25
BiTE® Antibody
The clinical effectiveness of BiTE® is currently being investigated
T cell
CD3
TAA-BiTE®-CD3
complex
TAA
MHC1
Cancer cell
BiTE® Antibodies are Designed to
Bridge Cancer Cells and CTLs
to Enable Cancer Cell Lysis
U
pon binding of both arms of investigational BiTE® antibodies,
BiTE®-activated T cells and cancer cells are forced within
close proximity of one another.22 As a result, a cytolytic synapse
is created between the T cell and cancer cell, perforin and
granzymes are released from the T cells, and target cell lysis
ensues. This activation is achieved independently of TCR
specificity, costimulation, or peptide antigen presentation.19
Cancer cell
Granzymes flowing
through perforin pore
Activated
caspase
Granzyme activation
of caspase
Inactive
caspase
The clinical effectiveness of BiTE® is currently being investigated
Fused
granule
CD3
T cell
TAA-BiTE®-CD3
complex
TAA
After target cell destruction, BiTE® antibodies are designed to move through the local
environment and target additional tumor cells.20 Cytotoxic T cells are not consumed
during lysis of target cells. After destruction of one tumor cell, an activated T cell can
move on to other tumor cells and initiate additional cell lysis.20 Activated T cells may also
release proinflammatory cytokines and produce even more perforin and granzyme to
support subsequent interactions to engage tumor cells.22,23 These mechanisms lead to
enhanced effects—a more complete elimination of tumor cell populations combined
than with each mechanism alone.
Investigational BiTE® Technology
T
he innate ability of T cells to target tumor cells supports the role for
the immune system in recognizing and suppressing tumor growth.
Through different mechanisms, tumor cells have the ability to escape T cell
immunosurveillance, BiTE® antibodies are designed to bridge CD3+ CTLs
to cells expressing cell-surface target antigens. In doing so, BiTE® represents
a new investigational approach to target different tumors throughout the body.
Apoptosis
The clinical effectiveness of BiTE® is currently being investigated
After target cell destruction through lysis,
BiTE® antibodies are designed to move
through the local environment and target
additional cells.
BiTE® Antibody
Mature T cell
References
1. Groscurth P, Filgueira L., News Physiol Sci. 1998; 13:17–21. 2. Weiner LM. N Engl J Med. 2008;358:2664–2665.
3. Ostrand-Rosenberg S, et al. J Immunol. 2009;182:4499–4506. 4. Töpfer K, et al. J Biomed Biotechnol.
2011;2011:918471. 5. Pardoll DM. Nat Rev Cancer. 2012;12:252–264. 6. Petersen SL. Dan Med Bull. 2007;54:
112–139. 7. Klyuchnikov E, et al. Bone Marrow Transplant. 2014;49:1–7. 8. Kanate AS, et al. World J Stem Cells.
2014;6:69–81. 9. Rezvani AR, et al. Curr Opin Hematol. 2013;20:509–514. 10. Rosenberg SA, et al. Nat Rev Cancer.
2008;8:299–308. 11. Pol JG, et al. Virus Adapt Treat. 2012;4:1–21. 12. Hawkins LK, et al. Lancet Oncol. 2002;3:
17–26. 13. Mullen JT, et al. Oncologist. 2002;7:106–119. 14. Fukuhara H, et al. Curr Cancer Drug Targets.
2007;7:149–155. 15. Hodi FS, et al. N Engl J Med. 2010;363:711–723. 16. Kantoff PW, et al. N Engl J Med.
2010;363:411–422. 17. Cartellieri M, et al. J Biomed Biotechnol. 2010;2010:956304. 18. Davila ML, et al.
Sci Trans Med. 2014;6:224ra25. 19. Baeuerle PA, et al. Cancer Res. 2009;69:4941–4944. 20. Hoffman P, et al.
Int J Cancer. 2005;115:98–104. 21. Frankel SR, et al. Curr Opin Chem Biol. 2013;17:385–392. 22. Nagorsen D, et
al. Exp Cell Res. 2011;317:1255–1260. 23. Baeuerle PA, Kufer P, et al. Curr Opin Mol Ther. 2009;11:22–30. 24.
Dreier T, et al. Int J Cancer. 2002;100: 690–697. 25. Offner S, et al. Mol Immunol. 2006;43:763–771.
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