alnuctamab (CC-93269)

P1/2, N=156, Recruiting, Celgene | Not yet recruiting --> Recruiting | Trial primary completion date: Dec 2027 --> Feb 2032

P3, N=466, Not yet recruiting, Celgene

P1, N=111, Recruiting, Juno Therapeutics, Inc., a Bristol-Myers Squibb Company | Not yet recruiting --> Recruiting

P1/2, N=156, Not yet recruiting, Celgene

P1, N=250, Recruiting, Celgene | Trial completion date: Aug 2027 --> Aug 2029

P1, N=250, Recruiting, Celgene | Trial completion date: Aug 2029 --> Aug 2027 | Trial primary completion date: Jun 2029 --> Jul 2027

P1, N=111, Not yet recruiting, Juno Therapeutics, Inc., a Bristol-Myers Squibb Company

P1, N=250, Recruiting, Celgene | Trial completion date: Aug 2027 --> Aug 2029 | Trial primary completion date: Jul 2027 --> Jun 2029

Introduction: T cell exhaustion (Tex) is characterized by progressive decline in activation and proliferation and has been implicated as a major resistance mechanism of T cell immunotherapies such as BCMA directed bispecifics approved for the treatment of multiple myeloma (MM). We demonstrated here that Aiolos/Ikaros regulate and maintain T cell exhaustion. Mezi mediated degradation of both transcription factors at the same time resulted in enhanced proinflammatory cytokine expression and reduction of exhaustion associated markers, as well as enhanced Tex killing of BCMA expressing tumor cells in combination with Alnuctamab.

We evaluated the anti-MM potential of ALNUC + pomalidomide (POM) and novel CELMoD agents mezigdomide (MEZI) and iberdomide (IBER) in preclinical models. To evaluate effects of CELMoD agents on ALNUC-mediated T cell anti-MM activity, healthy donor (HD) T cells and/or BCMA-expressing MM cell lines were pretreated with POM, MEZI, IBER, or DMSO for 16 h (T cells) or 72 h (MM cells) prior to coculture; ALNUC was added for 72 h and T cell activation and MM target cell depletion were measured. Combining ALNUC with novel CELMoD agents enhanced T cell mediated antitumor activity in both in vitro and ex vivo MM models. MEZI showed the greatest ability to enhance TCE-mediated antitumor activity while reversing artificial T cell dysfunction/exhaustion. Priming and concurrent treatment with MEZI enhanced ALNUC-induced T cell infiltration and activation in a MM xenograft model.

These BsAb show impressive clinical activity for the relapsed/refractory population targeted and will likely become an essential part of MM treatment protocols in the future. In this podcast, the authors summarize and highlight some of the T cell-redirecting BsAb currently in development for the treatment of relapsed/refractory MM with a focus on the data reported at the oral session for BsAb at the American Society of Hematology's 2022 meeting from clinical phase 1 and 2 studies. The six presentations reported the latest safety and efficacy data for the BsAb: talquetamab, elranatamab, teclistamab, forimtamig, and alnuctamab.

Despite promising efficacy in MM, BsAbs may come with substantial infection risk, warranting more detailed analysis of infections and immune phenotyping to guide targeted supportive care. Table – Summary of included studiesAgent Target Source Phase Enrolment (mm/yy) N Median prior lines All- Grade Infection N (%) Grade ≥3 Infection N (%) Alnuctamab (CC-93269) BCMA Wong 2022 I 03/18- 68 4 23 (34) 6 (9) ABBV-383 BCMA Voorhees 2022 I 10/22- 174 5 61/124 (50) 39/124 (22) Elranatamab BCMA Raje 2022 I 10/21- 123 5 82 (67) 43 (35) Linvoseltamab (REGN545) BCMA Bumma 2022 Ib/II 1/19- 252 5 136 (54) 73 (29) Pacanalotamab (AMG-420) BCMA Topp 2020 I 3/19 – 4/22 42 5 14 (33) 10 (24) Teclistamab BCMA Moreau 2022 I/II 09/20- 165 5 126 (77) 57 (45) Teclistamab + daratumumab BCMA + CD38 Rodriguez- Otero 2022 II 03/21- 46 5 29 (63) 8 (17) Forimtamig (RG6234) GPRC5D Carlo- Stella 2022 I 11/20- IV: 51 SC: 57 IV: 5 SC: 4 IV: 31 (61) SC: 26 (46) IV:11 (22) SC:15 (27) Talquetamab GPRC5D Chari 2022 I/II 02/21- 288 5 153 (53) 46 (16) Talquetamab + daratumumab GPRC5D + CD38 Van de Donk 2022 II 09/21- 46 5 23 (50) 6 (13) Cevostamab (BFCR4350A) FcRH5 Trudel 2021 I 07/21- 161 6 68 (43) 18 (11) Bispecific, Multiple myeloma, Cellular therapy

Aims: Evaluate the anti-MM potential of ALNUC+pomalidomide (POM) and novel CELMoD agents mezigdomide (MEZI) and iberdomide (IBER) in preclinical models. The combination of ALNUC with novel CELMoD agents showed enhanced T cell mediated antitumor activity in both in vitro and ex vivo MM models. MEZI showed the greatest ability to enhance TCE-mediated antitumor activity while reversing artificial T cell dysfunction/exhaustion in vitro. Priming and concurrent treatment withMEZI enhanced ALNUC-induced T cell infiltration and activation in a MM xenograft model.

IV ALNUC in C1 induced transient and dose-dependent secretion of soluble factors and cytokines associated with T-cell antitumor activity and CRS. SC dosing reduced and delayed the secretion of factors correlated with G ≥3 CRS. Plasma exposure to initial SC doses was lower than IV ALNUC; however, the target dose of 30 mg achieved predicted optimal exposure for efficacy.

All CRS events were G1 (44%; 32/73) or G2 (12%; 9/73); 35 (48%) pts received ≥1 concomitant medication for CRS, including tocilizumab (30%; 22/73) and/or corticosteroids (15%; 11/73). IV ALNUC continued to demonstrate durable responses in heavily pretreated pts with RRMM. SC administration improved the safety profile vs IV ALNUC, with CRS limited to low-grade, short-lived events. SC ALNUC exhibited promising dose-dependent antitumor activity and a high proportion of responders achieved MRD negativity.

T-cell-engaging therapeutical antibodies, such as Talquetamab (targeting GPRC5D and CD3 with 1:1 formation) and CC-93269(targeting BCMA and CD3 with 2:1 formation) have shown promise in multiple myeloma (MM) treatment. In addition, owning to the low affinity to CD3, MBS314 has no detectable toxicity in CD3 humanized mice. In summary, our data show MBS314 is a promising TCE for MM treatment with high efficacy and broad spectrum targeting both GPRC5D and BCMA, and also has excellent safety with low CD3 binding affinity.

Using preclinical models of MM, we evaluated the anti-MM potential of ALNUC in combination with pomalidomide (POM) and the novel CELMoD agents mezigdomide (MEZI; BMS-986348; CC-92480) and iberdomide (IBER). The combination of ALNUC and novel CELMoD agents demonstrated enhanced T cell mediated antitumor activity both in vitro and in ex vivo MM models. MEZI showed the greatest ability to enhance TCE-mediated antitumor activity while reversing artificial T cell dysfunction/exhaustion in vitro. Priming and concurrent treatment with MEZI enhanced ALNUC-induced T cell infiltration and activation in the MM xenograft model.

Background: Alnuctamab (ALNUC; BMS-986349; CC-93269) is an asymmetric 2-arm, humanized IgG TCE that binds to B-cell maturation antigen (BCMA) and CD3ε in a 2+1 format...Cells were pretreated overnight (~17 h) with clinically relevant concentrations of lenalidomide (LEN), pomalidomide (POM), iberdomide (IBER), mezigdomide (MEZI; BMS-986348; CC-92480), or dimethyl sulfoxide (DMSO), then stimulated with lipopolysaccharide (LPS) or anti-CD3/-CD28 beads to trigger cytokine release... CELMoD agents can suppress secretion of the proinflammatory cytokines IL-6 and IL-1β by monocytes/macrophages and PBMCs in vitro, with the strongest suppression observed with MEZI. In an ex vivo co-culture system of PBMCs with BCMA-expressing target cells, pretreatment with MEZI suppressed ALNUC-induced secretion of IL-6 and IL-1β, but not secretion of T cell-mediated cytokines. Our data demonstrate strong reductions in proinflammatory myeloid cell-derived cytokines by CELMoD agents while maintaining these agents' pro-immune properties, suggesting that potent CELMoD agents such as MEZI have the potential to mitigate CRS in patients with MM receiving TCEs.

Donor T cells (n = 3) or target MM cells (n = 3 cell lines with various BCMA-expression levels tested: H929 > OPM2 > L363) were pretreated with mezigdomide for 16 or 72 hours, respectively, and after mezigdomide wash off, T cells and MM cells were combined in a co-culture system followed by alnuctamab treatment for 72 hours...These results were reproducible across 3 healthy donors and various MM cell lines, including lenalidomide- and pomalidomide-resistant derivates, but not in CRBN-deficient cell lines... Collectively, our data demonstrate that pretreatment with mezigdomide induces enhanced immune sensitization in MM cells via upregulation of membrane-associated cell-adhesion molecules leading to increased cytotoxic T-cell activity. These results support the clinical investigation of mezigdomide in combination with T-cell-engaging therapeutic modalities in patients with MM.

Plasma exposure to initial SC doses was lower than IV ALNUC; however, the target dose achieved predicted optimal exposure for efficacy. These results suggest that SC formulation widens the therapeutic index of ALNUC, enabling higher target doses to be tested to increase efficacy while reducing release of proinflammatory cytokines and CRS-related toxicity.

Several phase 1, dose-escalation studies show pronounced activity of BCMA-targeting bispecific antibodies, including teclistamab, AMG420 and CC-93269, in heavily pretreated MM patients. Cytokine release syndrome is the most common adverse event, which can be adequately managed with tocilizumab or steroids...GPRC5D, CD38 and FcRH5), are also evaluated in early phase clinical trials. Such bispecific antibodies, targeting other antigens, may be given to patients with low baseline BCMA expression, disease with substantial heterogeneity in BCMA expression, following prior BCMA-targeted therapy, or combined with BCMA bispecific antibodies to prevent development of antigen escape.

CC-93269 antitumor activity was further explored in vivo using a PBMC-transferred humanized, lenalidomide-resistant H929-1051 MM xenograft mouse model...Co-treatment with clinically relevant doses of dexamethasone (DEX; 1 µM) lowered CC-93269-mediated release of IL-2 (by 48.3–74.1%), GM-CSF (by 47.5–67.8%) and TNF-α (by 46.3–61.8%), while minimally affecting CD4 and CD8 T cell activation, proliferation, and redirected lysis of BCMA+ MM cell lines...DEX attenuated cytokine release without affecting CC-93269 antitumor activity. A first-in-human study of CC-93269 in pts with RRMM is ongoing (NCT03486067), showing promising results, and additional clinical trials are planned to start this year.