Combination of T cell-redirecting bispecific antibody ERY974 and chemotherapy reciprocally enhances efficacy against non-inflamed tumours

Sano, Yuji; Azuma, Yumiko; Tsunenari, Toshiaki; Kayukawa, Yoko; Shinozuka, Junko; Fujii, Etsuko; Amano, Jun; Nishito, Yukari; Maruyama, Toru; Kinoshita, Yasuko; Sakamoto, Yuichiro; Yoshida, A; Miyazaki, Yoko; Sato, Yuta; Teramoto-Seida, Chifumi; Ishiguro, Takahiro; Tanaka, Takayoshi; Kitazawa, Takio; Endo, Mika

doi:10.1038/s41467-022-32952-3

Cited by 5 publications

(6 citation statements)

References 47 publications

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“…The authors characterised one of their tumour models as non-inflamed based on low immune cell infiltration. As expected ERY974 monotherapy had little effect on this model, but the addition of chemotherapeutic agent capecitabine improved accumulation of both T-cells and ERY974 in the tumour [ 33 ]. The benefit of this combination is bidirectional as ERY974 upregulated thymidine phosphorylase, an enzyme key for the conversion of capecitabine into its active form 5-fluorouracil [ 33 ].…”

Section: Chemotherapymentioning

confidence: 57%

“…As expected ERY974 monotherapy had little effect on this model, but the addition of chemotherapeutic agent capecitabine improved accumulation of both T-cells and ERY974 in the tumour [ 33 ]. The benefit of this combination is bidirectional as ERY974 upregulated thymidine phosphorylase, an enzyme key for the conversion of capecitabine into its active form 5-fluorouracil [ 33 ]. Capecitabine has previously been combined with other thymidine phosphorylase-inducing therapies to increase the effectiveness of chemotherapy [ 35 ], thus combination with ERY974 is a promising strategy.…”

Section: Chemotherapymentioning

confidence: 57%

“…Chemotherapy may increase tumour immunogenicity and therefore acts synergistically with immunotherapy, most notably CPIs [ 32 ]. This synergy also extends to BiTE therapy, which often fails due to immune-cold environments [ 33 ]. Polyclonal T-cell recruitment is an inherent feature of CD3-targeted BiTEs, and immunosuppressive Tregs are included within this population [ 4 ].…”

Section: Chemotherapymentioning

confidence: 99%

“…Preclinical data suggests that ERY974, a CD3xGPC3 BiTE, pairs synergistically with chemotherapy in mouse models of solid tumours [ 33 ]. The authors characterised one of their tumour models as non-inflamed based on low immune cell infiltration.…”

Section: Chemotherapymentioning

confidence: 99%

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Combination therapies for the optimisation of Bispecific T-cell Engagers in cancer treatment

Zhu

Middleton

2023

Immunotherapy Advances

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Bispecific T-cell engagers (BiTEs) redirect endogenous T-cell populations to cells expressing tumour associated antigens to induce tumour cell killing. This inherently relies upon a cytotoxic T-cell population that is able to be recruited. In many cancers, immune checkpoints and other immunosuppressive factors in the tumour microenvironment lead to a population of anergic T-cells which cannot be redirected to tumour killing and thus impede the efficacy of BiTE therapy. Furthermore, there is evidence that BiTE therapy itself can increase immune checkpoint expression, and this is thought to be a major escape mechanism for the BiTE therapy blinatumomab. To overcome these inadequate T-cell responses, BiTEs may be combined with checkpoint inhibitors, chemotherapy, costimulatory molecules or oncolytic viruses. Study of these combinations is needed to expand the use of BiTEs in solid malignancies. This review covers the rationale, preclinical evidence and any clinical trials for these combination therapies and a few other less studied combinations.

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Section: Chemotherapymentioning

confidence: 57%

Section: Chemotherapymentioning

confidence: 57%

Section: Chemotherapymentioning

confidence: 99%

Section: Chemotherapymentioning

confidence: 99%

See 2 more Smart Citations

Combination therapies for the optimisation of Bispecific T-cell Engagers in cancer treatment

Zhu

Middleton

2023

Immunotherapy Advances

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“… 205 , 393 Additionally, direct targeting of HCC TAAs using bsAbs, such as CD3×GPC3 TCE ERY974, can be an effective approach. 664 …”

Section: Discussionmentioning

confidence: 99%

Development of pharmacological immunoregulatory anti-cancer therapeutics: current mechanistic studies and clinical opportunities

Yin,

Li,

Zhang

et al. 2024

Sig Transduct Target Ther

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Immunotherapy represented by anti-PD-(L)1 and anti-CTLA-4 inhibitors has revolutionized cancer treatment, but challenges related to resistance and toxicity still remain. Due to the advancement of immuno-oncology, an increasing number of novel immunoregulatory targets and mechanisms are being revealed, with relevant therapies promising to improve clinical immunotherapy in the foreseeable future. Therefore, comprehending the larger picture is important. In this review, we analyze and summarize the current landscape of preclinical and translational mechanistic research, drug development, and clinical trials that brought about next-generation pharmacological immunoregulatory anti-cancer agents and drug candidates beyond classical immune checkpoint inhibitors. Along with further clarification of cancer immunobiology and advances in antibody engineering, agents targeting additional inhibitory immune checkpoints, including LAG-3, TIM-3, TIGIT, CD47, and B7 family members are becoming an important part of cancer immunotherapy research and discovery, as are structurally and functionally optimized novel anti-PD-(L)1 and anti-CTLA-4 agents and agonists of co-stimulatory molecules of T cells. Exemplified by bispecific T cell engagers, newly emerging bi-specific and multi-specific antibodies targeting immunoregulatory molecules can provide considerable clinical benefits. Next-generation agents also include immune epigenetic drugs and cytokine-based therapeutics. Cell therapies, cancer vaccines, and oncolytic viruses are not covered in this review. This comprehensive review might aid in further development and the fastest possible clinical adoption of effective immuno-oncology modalities for the benefit of patients.

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Bispecific Nanobody‐Aptamer Conjugates for Enhanced Cancer Therapy in Solid Tumors

Wang,

Chen,

Zhang

et al. 2024

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Bispecific antibodies possess exceptional potential as therapeutic agents due to their capacity to bind to two different antigens simultaneously. However, challenges pertain to unsatisfactory stability, manufacturing complexity, and limited tumor penetration hinder their broad applicability. In this study, a versatile technology is presented for the rapid generation of bispecific nanobody‐aptamer conjugates with efficient tumor penetration. The approach utilizes microbial transglutaminase (MTGase) and click chemistry to achieve site‐specific conjugation of nanobodies and aptamers, which are termed nanotamers. The nanotamers recognize and bind to two types of molecular targets expressed on cancer cells. As a prototype, a bispecific nanotamer is developed that binds both clusters of differentiation 47 (CD47) and mesenchymal epithelial transition receptor (Met) expressed on the tumor cell membrane. This CD47‐Met nanotamer demonstrates high affinity and specificity toward tumor cells expressing both targets, exhibits improved receptor functional inhibition through a strong steric hindrance effect. Moreover, its capacity for deep tumor penetration greatly enhances the impact of conventional chemotherapy on antitumor efficacy. The as‐developed nanotamer synthesis approach shows promise to customize bispecific molecular probes targeting different cancer types and different therapeutic goals.

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Combination of T cell-redirecting bispecific antibody ERY974 and chemotherapy reciprocally enhances efficacy against non-inflamed tumours

Cited by 5 publications

References 47 publications

Combination therapies for the optimisation of Bispecific T-cell Engagers in cancer treatment

Combination therapies for the optimisation of Bispecific T-cell Engagers in cancer treatment

Development of pharmacological immunoregulatory anti-cancer therapeutics: current mechanistic studies and clinical opportunities

Bispecific Nanobody‐Aptamer Conjugates for Enhanced Cancer Therapy in Solid Tumors

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