Duration: 5
min
Jeffery Shi
Protein and Antibody Product Marketing
Jeffrey Shi, Head of Protein and Antibody Product Marketing Team of Marketing
Department. He and his team are responsible for customer-centric development of full product
life cycle management for Protein and Antibody, and drive the sustainable development of the
protein antibody business.
Introduction
Bispecific antibodies (BsAbs) represent a breakthrough in medical science, offering
enhanced therapeutic potential through their ability to simultaneously target two distinct antigens or
epitopes. Unlike traditional monoclonal antibodies, BsAbs can redirect immune cells to tumor cells,
recruit other immune effector functions, block multiple disease pathways, and bridge molecules, thereby
increasing treatment specificity and efficacy while reducing off-target effects. This dual-targeting
capacity has shown significant promise in treating complex diseases such as cancer, autoimmune
disorders, and neurodegenerative conditions. Their enhanced efficacy, reduced toxicity, and
cost-effectiveness position BsAbs as a cornerstone for future targeted therapies and precision medicine.
Concept
Advances in antibody engineering have led to bispecific antibodies (bsAbs), which can bind to two
different antigens or epitopes on the same antigen[1]. Conceptualized in the 1960s[2],
bsAbs are particularly
useful in cancer immunotherapy and other areas, including chronic inflammatory and autoimmune diseases,
neurodegenerative disorders, vascular issues, ocular conditions, hematologic disorders, and
infections[3].
Although bsAbs hold significant therapeutic potential, their production is challenging.
Figure 1 Classical molecular platform of BsAbs and representative
antibodies.
Adapted from Ma et al., Front. Immunol. 12:666 (2021). DOI: 10.3389/fimmu.2021.626616.
Mechanisms of Action
In order to comprehend the full scope of the potential inherent in bispecific antibodies,
it
is imperative to delve into the mechanisms through which they achieve their therapeutic effects. The
multifaceted actions of bispecific antibodies are intricately linked to their design and intended
applications. These innovative molecules have the capacity to bind to two distinct antigens, thus
enabling a
variety of therapeutic strategies. Common mechanisms include the redirection of immune cells to target
cancer cells, the obstruction of signaling pathways that are critical for disease progression, and the
delivery of therapeutic agents directly to specific cells. A comprehensive understanding of these
mechanisms
is paramount to leveraging the full potential of bispecific antibodies in diverse medical disciplines.
Redirecting Immune Cells to Tumor Cells:
The majority of bispecific antibodies (bsAbs) in clinical trials work as CD3 T cell
engagers
(TCEs). These bsAbs have the unique ability to bind to both the CD3 molecule on T cells and a
tumor-associated antigen (TAA) on tumor cells. By attaching to these two targets simultaneously, bsAbs
bring
T cells into close contact with tumor cells. This close proximity allows for the formation of an immune
synapse, which activates the T cells and directs their cytotoxic activity specifically against the tumor
cells[4].
However, CD3 bsAbs demonstrate a limited capacity to kill tumor cell. The effectiveness and
specificity of these antibodies are contingent upon their ability to form a three-part structure
(trimer)
that incorporates the bsAb, a T cell, and a tumor cell[5]. A prominent example of this
therapeutic modality is blinatumomab (Blincyto), which targets CD19 on B cells and CD3 on T cells. This
interaction facilitates the effective elimination of cancer cells by T cells.
Figure 2 Mechanisms of action of bispecific antibodies
(bsAbs).
Adapted from Herrera et al., Trends in Cancer 10:893–919 (2024). DOI:
10.1016/J.TRECAN.2024.07.002.
Recruiting Other Immune Effector Functions:
In addition to T cells, bispecific antibodies (bsAbs) can also attract other types of immune cells
to
attack tumors. One example is natural killer (NK) cells, which are powerful cells in our innate immune system
capable of destroying harmful cells. For instance, there is a bispecific antibody called AFM-13 that is being
tested
in phase II clinical trials for patients with Hodgkin’s lymphoma. AFM-13 is specially designed to connect to
CD16 on
NK cells and CD30 on tumor cells. By doing this, AFM-13 brings NK cells directly to the tumor cells. This
connection
helps NK cells to recognize and kill the tumor cells effectively, a process known as antibody-dependent cellular
cytotoxicity (ADCC)[6].
Blocking Multiple Pathways:
Some bi-specific antibodies (bsAbs) are designed to simultaneously block two different pathways
that
are important for disease progression. This strategy can be particularly helpful in treating diseases such as
cancer, where multiple pathways typically play a role in tumor growth and survival. By targeting two pathways
simultaneously, bsAbs can provide a more thorough therapeutic effect.
For example, a bi-specific antibody can simultaneously inhibit two signaling pathways that are necessary for
tumor
cell growth and the formation of new blood vessels (angiogenesis). This dual action can suppress tumor growth
and
spread more effectively than antibodies that target only one pathway[7].
Bridging Molecules:
Bispecific antibodies (bsAbs) possess the distinctive capacity to link distinct types of cells or
molecules, thereby potentiating their combined effects and modulating various biological processes. For
instance,
bsAbs can bind antigen-presenting cells (APCs) with T cells, thereby enhancing antigen presentation and
activating T
cells, thus enhancing the efficiency of the immune response [8]. Moreover, bsAbs can bind a cytokine
with
its receptor or an enzyme with its substrate. This binding modality can either augment or impede the functions
of
the linked molecules, thereby regulating diverse biological processes[9].
Advantages of Bispecific Antibodies
By leveraging unique mechanisms of action, such as redirecting immune cells to tumor cells,
recruiting
other immune effector functions, blocking multiple pathways, and bridging molecules, bispecific antibodies not
only
demonstrate significant therapeutic potential but also offer several advantages over traditional monoclonal
antibodies. These innovative agents have the capacity to target two distinct antigens in a simultaneous manner,
thereby enhancing specificity and efficacy while concomitantly reducing off-target effects. This dual-targeting
capability allows for more precise engagement of the immune system, making bispecific antibodies a powerful tool
in
the fight against cancer and other diseases.
Enhanced Efficacy:
Bispecific antibodies (BsAbs) have the capacity to bind to both a target antigen and an effector
cell
marker antigen, thereby effectively mediating immune cell killing. This dual-binding mechanism activates
effector
cells to target and destroy tumor cells.
For example, blinatumomab (Blincyto) is a CD19 × CD3 bispecific antibody that redirects T cells to
kill
B-cell leukemia cells by simultaneously binding CD19 on tumor cells and CD3 on T cells[10]. This
mechanism has been
validated in clinical trials and is the basis for the success of several bsAbs in cancer immunotherapy.
Preventing Drug Resistance:
Bispecific antibodies (BsAbs) can simultaneously bind to two targets, blocking dual signaling
pathways.
Receptor tyrosine kinases (RTKs), like the HER family, are critical for cell proliferation and are often
overexpressed in tumor cells, leading to uncontrolled growth. The HER family, which includes several proteins,
such
as HER1 (also known as EGFR), HER2, HER3, and HER4, is involved in cell signaling pathways that control growth
and
division[11].
Conventionally, monoclonal antibodies (mAbs) have been known to target a single RTK. However, tumor
cells have been observed to evade detection by altering signaling pathways or by forming dimers with other HER
family members or disparate RTKs. Consequently, if one pathway is blocked, the tumor cells can use alternative
pathways to continue growing [12].
BsAbs address this challenge by blocking two or more RTKs or their ligands simultaneously, thereby
preventing the tumor cells from using these alternative pathways. This approach reduces tumor cell escape and
enhances treatment efficacy, making BsAbs a powerful tool in cancer therapy[11].
Reduced Toxicity:
The two antigen-binding arms of bispecific antibodies (BsAbs) can target different antigens. By
binding
to two antigens on the surface of cancer cells, BsAbs enhance the binding specificity and targeting of
antibodies to
cancer cells, thereby reducing off-target effects and associated side effects.
This dual-targeting mechanism allows BsAbs to achieve higher specificity and efficacy than
traditional
monoclonal antibodies. For example, cis-targeting bispecific antibodies (bsAbs) can engage two distinct targets
on
the same cell surface, thereby increasing target selectivity and reducing the likelihood of off-target
interactions[13]. This approach has been shown to be particularly effective in cancer therapy, where
the
ability to
precisely target tumor cells is crucial to minimize collateral damage to healthy tissues.
Figure 3 Features of bispecific antibody (bsAb) targeting.
Adapted from Oslund et al., Cell Chemical Biology 31:1473–1489 (2024). DOI:
10.1016/J.CHEMBIOL.2024.07.004.
Cost-Effectiveness:
In comparison with traditional antibodies, bispecific antibodies (bsAbs) have significant
advantages,
including better tissue penetration, higher tumor cell killing efficiency, lower off-target effects, and broader
clinical applications. One key benefit is their potency; bsAbs can be 100 to 1000 times more effective than
regular
antibodies. This allows for much smaller doses—up to 1/2000 of the original amount—significantly reducing
treatment
costs. Furthermore, bsAbs are more cost-effective than combination therapies, as they eliminate the need for
using
two separate drugs.
Applications of Bispecific Antibodies
While bispecific antibodies (bsAbs) have shown great promise in cancer therapy, their applications
extend beyond oncology into other areas of medicine. In fact, the unique ability of bsAbs to simultaneously
target
two different antigens provides a versatile platform for treating a wide range of diseases. This dual-targeting
mechanism not only increases the specificity and efficacy of treatments, but also opens up new possibilities for
the
treatment of autoimmune diseases, infectious diseases and even neurological disorders.
Figure 4 Timeline showing development of therapeutic antibodies and bispecific
Abs.
Adapted from Lim et al., Cancer Treatment Reviews 99:102240 (2021). DOI:
10.1016/J.CTRV.2021.102240.
Redirecting T-Cells to Cancer Cell:
Bispecific antibodies can be designed to redirect T-cells to cancer cells by simultaneously binding
to
a tumor-associated antigen and the CD3 protein on T-cells. An example of this is the development of talquetamab,
a
GPRC5D-targeting bispecific antibody approved for the treatment of multiple myeloma[14]. Talquetamab
binds to GPRC5D
on cancer cells and CD3 on T-cells, effectively recruiting T-cells to the tumor site and promoting cancer cell
destruction. This approach has shown significant efficacy in clinical trials, leading to improved outcomes for
patients with relapsed or refractory multiple myeloma[14].
HIV-1 Reservoir Elimination:
Researchers are studying bispecific antibodies as a way to get rid of HIV-1 reservoirs, which are a
major barrier to curing HIV infection. One innovative approach involves using bispecific antibodies to engage
natural killer (NK) cells to target HIV-1-infected cells. These antibodies target the HIV-1 envelope protein and
the
human type III Fcγ receptor (CD16) to enhance NK cell activation and cytotoxicity against HIV-1-infected cells.
Studies have shown that this approach can effectively eliminate HIV-1 reservoir cells both in vitro and in mouse
models[15].
Neurodegenerative Disease Therapy:
Another emerging application of bispecific antibodies is in the treatment of neurodegenerative
diseases, such as Alzheimer's disease. These antibodies can be engineered to target amyloid-beta plaques and
recruit
immune cells to clear these toxic aggregates from the brain. Additionally, bsAbs can be designed to
simultaneously
target multiple pathological proteins involved in neurodegeneration, such as tau and alpha-synuclein, thereby
providing a more comprehensive therapeutic strategy[16]. While clinical trials in this domain remain
sparse,
preclinical studies have demonstrated encouraging results, including the reduction of amyloid plaque burden and
the
enhancement of cognitive function.
Conclusion
Bispecific antibodies are a breakthrough in medical science, offering superior efficacy, reduced
toxicity, and versatile clinical applications over traditional monoclonal antibodies. Their ability to
simultaneously target two antigens enhances immune cell engagement, blocks multiple disease pathways, and
increases
treatment specificity. These attributes make bispecific antibodies a promising tool for treating complex
diseases
such as cancer, autoimmune diseases, and neurodegenerative conditions. As research and clinical trials continue,
bispecific antibodies are poised to play a pivotal role in the future of targeted therapies and precision
medicine.
References
[1] Ma, J. et al. Bispecific Antibodies: From Research to Clinical Application. Front. Immunol. 12,
666
(2021). https://doi.org/10.3389/fimmu.2021.626616.
[2] Nisonoff, A., Wissler, F. C., & Lipman, L. N. Properties of the major component of a peptic
digest
of rabbit antibody. Science 132, 1770 (1960). https://doi.org/10.1126/science.132.3441.1770.
[3] Brinkmann, U. & Kontermann, R. E. Bispecific antibodies. Science 372, 916–917 (2021).
https://doi.org/10.1126/science.abg1209.
[4] Betts, A., & van der Graaf, P. H. Mechanistic Quantitative Pharmacology Strategies for the
Early
Clinical Development of Bispecific Antibodies in Oncology. Clin Pharmacol Ther. 108, 528-541 (2020).
https://doi.org/10.1002/cpt.1961.
[5] Betts, A. et al. A Translational Quantitative Systems Pharmacology Model for CD3 Bispecific
Molecules: Application to Quantify T Cell-Mediated Tumor Cell Killing by P-Cadherin LP DART®. AAPS J. 21, 66
(2019).
https://doi.org/10.1208/s12248-019-0332-z.
[6] Rothe, A. et al. A phase 1 study of the bispecific anti-CD30/CD16A antibody construct AFM13 in
patients with relapsed or refractory Hodgkin lymphoma. Blood 125, 4024-31 (2015).
https://doi.org/10.1182/blood-2014-12-614636.
[7] Brinkmann, U., & Kontermann, R. E. The making of bispecific antibodies. MAbs 9, 182-212 (2017).
https://doi.org/10.1080/19420862.2016.1268307.
[8] Klein, C., Brinkmann, U., Reichert, J. M. et al. The present and future of bispecific
antibodies
for cancer therapy. Nat Rev Drug Discov 23, 301–319 (2024). https://doi.org/10.1038/s41573-024-00896-6.
[9] Segués, A., Huang, S., Sijts, A., Berraondo, P., & Zaiss, D. M. Opportunities and challenges of
bi-specific antibodies. International Review of Cell and Molecular Biology 369, 45–70 (2022).
https://doi.org/10.1016/BS.IRCMB.2022.05.001.
[10] Liao, C. Y., Engelberts, P., Ioan-Facsinay, A. et al. CD3-engaging bispecific antibodies
trigger a
paracrine regulated wave of T-cell recruitment for effective tumor killing. Commun Biol 7, 983 (2024).
https://doi.org/10.1038/s42003-024-06682-9.
[11] Herrera, M., Pretelli, G., Desai, J., Garralda, E., Siu, L. L., Steiner, T. M., & Au, L.
Bispecific antibodies: advancing precision oncology. Trends in Cancer 10, 893–919 (2024).
https://doi.org/10.1016/J.TRECAN.2024.07.002.
[12] Hosseini, S. S., Khalili, S., Baradaran, B., Bidar, N., Shahbazi, M. A., Mosafer, J.,
Hashemzaei,
M., Mokhtarzadeh, A., & Hamblin, M. R. Bispecific monoclonal antibodies for targeted immunotherapy of solid
tumors:
Recent advances and clinical trials. International Journal of Biological Macromolecules 167, 1030–1047 (2021).
https://doi.org/10.1016/J.IJBIOMAC.2020.11.058.
[13] Oslund, R. C., Holland, P. M., Lesley, S. A., & Fadeyi, O. O. Therapeutic potential of
cis-targeting bispecific antibodies. Cell Chemical Biology 31, 1473–1489 (2024).
https://doi.org/10.1016/J.CHEMBIOL.2024.07.004.
[14] Klein, C., Brinkmann, U., Reichert, J. M. et al. The present and future of bispecific
antibodies
for cancer therapy. Nat Rev Drug Discov 23, 301–319 (2024). https://doi.org/10.1038/s41573-024-00896-6.
[15] Board, N. L., Yuan, Z., Wu, F. et al. Bispecific antibodies promote natural killer
cell-mediated
elimination of HIV-1 reservoir cells. Nat Immunol 25, 462–470 (2024).
https://doi.org/10.1038/s41590-023-01741-5.
[16] Lim, S. M., Pyo, K. H., Soo, R. A., & Cho, B. C. The promise of bispecific antibodies: Clinical applications and challenges. Cancer Treatment Reviews 99, 102240 (2021). https://doi.org/10.1016/J.CTRV.2021.102240.
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