Co-localized Blocking

Bispecific antibodies (BsAbs) are a novel class of therapeutic agents that can simultaneously bind to two different antigens or epitopes, thereby achieving multiple functions and enhancing efficacy. BsAbs have been widely explored for cancer immunotherapy, as they can recruit and activate immune cells, block multiple signaling pathways, or modulate the tumor microenvironment. BsAbs have a long history of development, dating back to the 1960s when the concept of BsAbs was first proposed by Nisonoff and colleagues. Since then, various methods and technologies have been developed to produce BsAbs with different formats and characteristics. Currently, there are more than 30 commercial platforms for generating BsAbs, and more than 110 BsAbs are in clinical trials for various types of cancers. One of the specific mechanisms of BsAbs is co-localized blocking, which refers to the simultaneous inhibition of two or more signaling pathways that are involved in tumor growth, survival, invasion, angiogenesis, or resistance.

Principle of Co-localized Blocking

The basic principle of co-localized blocking BsAbs is to simultaneously inhibit two or more signaling pathways that are involved in tumor growth, survival, invasion, angiogenesis, or resistance. By blocking multiple targets on the same cell or in the same microenvironment, co-localized blocking BsAbs can achieve synergistic effects and overcome the limitations of single-targeted therapies. For example, some tumors can activate alternative or compensatory pathways to escape from the inhibition of one pathway, or develop mutations or amplifications that confer resistance to specific inhibitors. Co-localized blocking BsAbs can prevent or delay these mechanisms by targeting two or more key molecules in the same or parallel pathways.

Features of Co-localized Blocking

Co-localized blocking BsAbs have some distinctive features that differentiate them from other types of BsAbs with different mechanisms, such as cell bridging, dual immune checkpoint blockade, or tumor microenvironment modulation. Some of the features of Co-localized Blocking BsAbs are:

Higher selectivity and functionality: Co-localized blocking BsAbs can achieve higher selectivity and functionality by targeting two or more molecules that are co-expressed or co-activated on the same cell or in the same microenvironment. This can reduce the off-target toxicity and increase the therapeutic window of BsAbs. For example, amivantamab can selectively bind to tumor cells that express both EGFR and c-MET, while sparing normal cells that express only one of them. This can avoid the skin rash and diarrhea that are commonly associated with EGFR inhibitors.

Enhanced therapeutic effect: Co-localized blocking BsAbs can enhance the therapeutic effect by inhibiting multiple signaling pathways involved in tumor growth, survival, invasion, angiogenesis, or resistance. This can overcome the limitations of single-targeted therapies that may be ineffective or induce resistance. For example, faricimab can inhibit both VEGF and ANGPT2, which have synergistic roles in promoting pathological neovascularization and edema in the eye. This can achieve better and longer-lasting outcomes than ranibizumab, which only inhibits VEGF.

Complex structure design: Co-localized blocking BsAbs have a complex structure design that requires careful optimization and engineering. The structure of co-localized blocking BsAbs should ensure the appropriate binding affinity, specificity, valency, orientation, and stability of each arm. The structure should also avoid potential issues such as immunogenicity, aggregation, degradation, or cross-reactivity. For example, amivantamab has a unique asymmetric IgG1 structure that consists of a conventional heavy chain-light chain pair and a heavy chain-single chain variable fragment pair. This structure allows amivantamab to bind to both EGFR and c-MET with high affinity and specificity, while avoiding interference between the two arms.

Difficult dose control: Co-localized blocking BsAbs have difficult dose control that requires careful evaluation and adjustment. The dose of co-localized blocking BsAbs should balance the efficacy and safety of blocking multiple targets on the same cell or in the same microenvironment. The dose should also consider the pharmacokinetics, pharmacodynamics, biodistribution, and clearance of BsAbs. For example, faricimab has a longer half-life and slower clearance than ranibizumab. This means that faricimab can be administered less frequently than ranibizumab but also poses a higher risk of overblocking or adverse events.

Applications in Cancer Therapy of Co-localized Blocking

Co-localized blocking BsAbs have a wide range of applications in cancer therapy as they can target various combinations of signaling pathways involved in tumor growth, survival, invasion, angiogenesis, or resistance. Several co-localized blocking BsAbs have been approved or are under development for different types of cancers.

Table 1. Examples of Co-localized Blocking BsAbs

References

1. Spiess C,et al. Alternative molecular formats and therapeutic applications for bispecific antibodies. Mol Immunol. 2015 Oct;67(2 Pt A):95-106.
2. Labrijn AF, et al. Bispecific antibodies: a mechanistic review of the pipeline. Nat Rev Drug Discov. 2019 Aug;18(8):585-608.
3. Spiess C, et al. Bispecific antibodies with natural architecture produced by co-culture of bacteria expressing two distinct half-antibodies. Nat Biotechnol. 2013 Jul;31(7):647-9.
4. Lewis SM, et al. Generation of bispecific IgG antibodies by structure-based design of an orthogonal Fab interface. Nat Biotechnol. 2014 Feb;32(2):191-8.
5. Klein C, et al. Engineering therapeutic bispecific antibodies using CrossMab technology. Methods. 2019 Mar 1;154:21-31.
6. Schaefer W, et al. Immunoglobulin domain crossover as a generic approach for the production of bispecific IgG antibodies. Proc Natl Acad Sci U S A. 2011 Jul 12;108(28):11187-92.
7. Moore GL, et al. Engineered Fc variant antibodies with enhanced ability to recruit complement and mediate effector functions. MAbs. 2010 May-Jun;2(3):181-9.