To design drugs that have a broad therapeutic index by strongly targeting the disease while causing minimal injury to normal tissues still underpins the overarching goal of biopharmaceutical development. Antibody-drug conjugates (ADC) have been introduced into clinical practice in order to improve the efficacy of antibody-based targeted therapy. As a reliable antibody expert in the market, Creative Biolabs is focusing on cutting-edge bispecific antibody (BsAb) strategies that are currently under investigation and can provide a comprehensive portfolio of BsAb products to meet both the efficacy and safety aspects of ADC’s.
ADC is a complex immunoconjugate that one or more cytotoxic agents connected to a monoclonal antibody (mAb) by a covalent bond (linker). That aims to utilize the specificity of mAb to selectively deliver cytotoxic drugs preferentially to antigen-expressing tumor cells. The targeted delivery of cytotoxic drugs to cancer cells raises the percentage of drug molecules reaching the tumor, thus lowering the minimum effective dose and elevating the maximum tolerated dose. In contrast to traditional cytotoxic drugs, ADC can increase efficacy and decrease toxicity of its payloads.
ADC represents an innovative therapeutic approach that offers the promise for increased drug specificity and fewer off-target effects than chemotherapy. There’re several commercial drugs approved by FDA, like brentuximab vedotin for CD30-positive Hodgkin's lymphoma and trastuzumab emtansine for human EGFR2-positive breast cancer. This technology to therapy displays meaningful outcomes while potentially limiting side effects.
Despite the continual development of new therapies based on mAbs, in oncology, in particular, certain limitations to their diagnostic and therapeutic use remain. BsAbs are antibodies with two different paratopes, the principle of which is the targeting of two targets through a single framework to cover the multifactorial side of diseases and simultaneously affect multiple signaling pathways to enhance efficacy. In the last decade, advances in protein engineering have enabled the development of over 100 formats of BsAbs.
Fig.2 Schematic bispecific antibody formats. (Comer, 2018)
Recent examples have demonstrated how BsAbs can be exploited to generate ADCs with better efficacy and safety profile. And there’re two topical points in oncology for developing bispecifics: a, the direct targeting of two tumor antigens or two different epitopes on the same antigen (e.g. biparatopic antibody) playing a critical role at the origin of the pathology; b, the use of antibody as a vector permitting the redirection of molecular effectors (e.g. cytotoxic drugs, radionuclides) or cellular effectors of the immune system that lack Fc receptors and are not recruited by mAbs to target cells. Not all these means are adapted to ADC development and implemented to improve their pharmacological properties. But, in fact, it has been proved that ADC selectivity, internalization, payload delivery, and acquired resistance can be greatly benefited from bispecific approaches.
The type of bispecific technologies will likely start to be chosen more frequently for poorly internalizing tumor antigens where optimization of cytotoxic delivery requires higher tumor selectivity, enhanced ADC uptake, and more effective lysosomal trafficking. The strides made in antibody engineering coupled with strides made in ADC technology make this an ideal opportunity to develop bispecific ADCs with improved activity and better efficacy. Notably, Creative Biolabs has rich experience in the production of bispecific antibodies and can precisely modify new promising bispecific ADCs with quality controls.
Fig.3 Schematic mechanism of action of bispecific ADCs relying on fast internalizing receptors to migrate to the lysosome and deliver their payload. (Maruani, 2018)
The identification of BsAb formats with desired functionalities is important to develop bispecific ADCs. The choice of molecular format can confer key features, such as binding modality (i.e. monovalent or bivalent binding to each target). The conventional IgG, like the valent bispecific format, is usually selected for great developability properties, extended in vivo half-life, and desirable antibody effector functions (i.e ADCC and CDC). At Creative Biolabs, we’re able to provide many different BsAb formats as Fig.2 for ADC drug development, and further, assist clients in selecting the suitable binding modality to match the proposed mechanisms of action and the specific clinical applications.
The ideal target antigen for an ADC would be highly expressed only on diseased tissues, and unfortunately, it is a rare case to see. Accumulative evidence illustrated that BsAbs can improve the efficacy of ADC’s by enhancing targeting to lysosomes. At Creative Biolabs, we seek the bispecific technology to increase the ability of ADC targeting and selectivity. In its simplest form, BsAbs can employ dual targeting to extend the reach of an ADC, termed to create a two in one ADC. In this situation, either target is sufficient to deliver the ADC into tumor cells, which is useful to discriminate efficiently between healthy and diseased tissues for broad therapeutic benefit when the targets are heterogeneously expressed on the tumor.
ADCs are designed to be stable in circulation and to release potent cytotoxic drugs intracellularly following antigen-specific binding, uptake, and degradation in tumor cells. Besides high tumor selectivity, ADCs require efficient internalization and trafficking to lysosomes where proteolysis can take place and thus essential. To alleviate this limitation, Creative Biolabs has developed novel bispecific-based strategies and we have two main methods to promote endocytosis and lysosomal trafficking.
As a leading custom service provider industry leader in the field of antibody engineering, Creative Biolabs has gained great reputation worldwide by virtue of rigorous academic teams, advanced technique platforms, and considerate services. We’re able to capitalize on bispecific antibody technology to increase the therapeutic index of ADC’s. As well, our powerful ADC technology combines the specificity of bispecific antibodies, novel linker systems, and potent cell-killing agents that can fight various diseases, particularly cancers. We also support One-stop ADC Development Service for high-quality monoclonal antibodies and sincerely help clients address more challenging antibody projects. If there is any query, please contact us for more details.
1. Comer, F.; et al. Bispecific and biparatopic antibody drug conjugates. Innovations for Next-Generation Antibody-Drug Conjugates? 2018, 267-280.
2. Maruani, A. Bispecifics and antibody-drug conjugates: A positive synergy. Drug Discov Today Technol. 2018, 30: 55-61.